138 results on '"M. Gunel"'
Search Results
2. PATHOLOGY
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J.-i. Adachi, K. Totake, M. Shirahata, K. Mishima, T. Suzuki, T. Yanagisawa, K. Fukuoka, R. Nishikawa, A. Arimappamagan, N. Manoj, A. Mahadevan, D. Bhat, H. Arvinda, B. Indiradevi, S. Somanna, B. Chandramouli, S. A. Petterson, S. K. Hermansen, R. H. Dahlrot, S. Hansen, B. W. Kristensen, F. Carvalho, S. Jalali, S. Singh, S. Croul, K. Aldape, G. Zadeh, J. Choi, S.-H. Park, S. K. Khang, Y.-L. Suh, S. P. Kim, Y. S. Lee, S. H. Kim, S. Coberly, K. Samayoa, Y. Liu, P. Kiaei, J. Hill, S. Patterson, M. Damore, S. Dahiya, R. Emnett, J. Phillips, D. Haydon, J. Leonard, A. Perry, D. Gutmann, S. Epari, S. Ahmed, M. Gurav, S. Raikar, A. Moiyadi, P. Shetty, T. Gupta, R. Jalali, J. Georges, A. Zehri, E. Carlson, N. Martirosyan, A. Elhadi, J. Nichols, L. Ighaffari, J. Eschbacher, B. Feuerstein, T. Anderson, M. Preul, K. Jensen, P. Nakaji, H. Girardi, F. Monville, S. Carpentier, M. Giry, J. Voss, R. Jenkins, B. Boisselier, V. Frayssinet, C. Poggionovo, A. Catteau, K. Mokhtari, M. Sanson, H. Peyro-Saint-Paul, C. Giannini, T. Hide, H. Nakamura, K. Makino, S. Yano, S. Anai, N. Shinojima, J.-i. Kuroda, T. Takezaki, J.-i. Kuratsu, F. Higuchi, H. Matsuda, K. Iwata, K. Ueki, P. Kim, J. Kong, L. Cooper, F. Wang, J. Gao, G. Teodoro, L. Scarpace, T. Mikkelsen, M. Schniederjan, C. Moreno, J. Saltz, D. Brat, U. Cho, Y.-K. Hong, R. Lober, L. Lu, M. H. Gephart, P. Fisher, M. Miyazaki, H. Nishihara, T. Itoh, M. Kato, S. Fujimoto, T. Kimura, M. Tanino, S. Tanaka, N. Nguyen, G. Moes, J. L. Villano, H. Kanno, Y. Kato, T. Ohnishi, H. Harada, S. Ohue, S. Kouno, A. Inoue, D. Yamashita, S. Okamoto, M. Nitta, Y. Muragaki, T. Maruyama, T. Sawada, T. Komori, T. Saito, Y. Okada, S. B. Omay, J. M. Gunel, V. E. Clark, J. Li, E. Z. E. Omay, A. Serin, L. E. Kolb, R. M. Hebert, K. Bilguvar, K. Ozduman, M. N. Pamir, T. Kilic, J. Baehring, J. M. Piepmeier, C. W. Brennan, J. Huse, P. H. Gutin, K. Yasuno, A. Vortmeyer, M. Gunel, S. Pugh, C. L. Rogers, D. Brachman, W. McMillan, J. Jenrette, I. Barani, D. Shrieve, A. Sloan, M. Mehta, A. Prabowo, A. Iyer, T. Veersema, J. Anink, A. S.-v. Meeteren, W. Spliet, P. van Rijen, T. Ferrier, D. Capper, M. Thom, E. Aronica, T. Chharchhodawala, M. Sable, M. C. Sharma, C. Sarkar, V. Suri, M. Singh, V. Santosh, B. Thota, M. Srividya, K. Sravani, S. Shwetha, A. Arivazhagan, K. Thennarasu, A. Hegde, P. Kondaiah, K. Somasundaram, M. Rao, V. P. Kumar, A. Shastry, R. Narayan, S. Naz, S. Venneti, M. Garimella, L. Sullivan, D. Martinez, A. Heguy, M. Santi, C. Thompson, A. Judkins, Z. Voronovich, L. Chen, K. Clark, M. Walsh, J. Mannas, C. Horbinski, B. Wiestler, T. Holland-Letz, A. Korshunov, A. von Deimling, S. M. Pfister, M. Platten, M. Weller, W. Wick, G. Zieman, C. Dardis, and L. Ashby
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Abstracts ,Cancer Research ,Oncology ,Neurology (clinical) - Published
- 2013
3. OMICS AND PROGNSTIC MARKERS
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K. Adachi, H. Sasaki, S. Nagahisa, K. Yoshida, N. Hattori, Y. Nishiyama, T. Kawase, M. Hasegawa, M. Abe, Y. Hirose, A. Alentorn, Y. Marie, S. Poggioli, H. Alshehhi, B. Boisselier, C. Carpentier, K. Mokhtari, L. Capelle, D. Figarella-Branger, K. Hoang-Xuan, M. Sanson, J.-Y. Delattre, A. Idbaih, S. Yust-Katz, M. Anderson, A. Olar, A. Eterovic, N. Ezzeddine, K. Chen, H. Zhao, G. Fuller, K. Aldape, J. de Groot, N. Andor, J. Harness, S. G. Lopez, T. L. Fung, H. W. Mewes, C. Petritsch, A. Arivazhagan, K. Somasundaram, K. Thennarasu, P. Pandey, B. Anandh, V. Santosh, B. Chandramouli, A. Hegde, P. Kondaiah, M. Rao, R. Bell, R. Kang, C. Hong, J. Song, J. Costello, R. Nagarajan, B. Zhang, A. Diaz, T. Wang, L. Bie, Y. Li, H. Liu, W. F. C. Luyo, M. H. Carnero, M. E. P. Iruegas, A. R. Morell, M. C. Figueiras, R. L. Lopez, C. F. Valverde, A. K.-Y. Chan, J. C.-S. Pang, N. Y.-F. Chung, K. K.-W. Li, W. S. Poon, D. T.-M. Chan, Y. Wang, H.-a. K. Ng, M. Chaumeil, P. Larson, H. Yoshihara, D. Vigneron, S. Nelson, R. Pieper, J. Phillips, S. Ronen, V. Clark, Z. E. Omay, A. Serin, J. Gunel, B. Omay, C. Grady, M. Youngblood, K. Bilguvar, J. Baehring, J. Piepmeier, P. Gutin, A. Vortmeyer, C. Brennan, M. N. Pamir, T. Kilic, B. Krischek, M. Simon, K. Yasuno, M. Gunel, A. L. Cohen, M. Sato, K. D. Aldape, C. Mason, K. Diefes, L. Heathcock, L. Abegglen, D. Shrieve, W. Couldwell, J. D. Schiffman, H. Colman, Q. G. D'Alessandris, T. Cenci, M. Martini, L. Ricci-Vitiani, R. De Maria, L. M. Larocca, R. Pallini, B. Theeler, F. Lang, G. Rao, M. Gilbert, E. Sulman, R. Luthra, K. Eterovic, M. Routbort, R. Verhaak, G. Mills, J. Mendelsohn, F. Meric-Bernstam, A. Yung, K. MacArthur, S. Hahn, G. Kao, R. Lustig, M. Alonso-Basanta, S. Chandrasekaran, E. P. Wileyto, E. Reyes, J. Dorsey, K. Fujii, K. Kurozumi, T. Ichikawa, M. Onishi, J. Ishida, Y. Shimazu, B. Kaur, E. A. Chiocca, I. Date, C. Geisenberger, A. Mock, R. Warta, C. Schwager, C. Hartmann, A. von Deimling, A. Abdollahi, C. Herold-Mende, O. Gevaert, A. Achrol, S. Gholamin, S. Mitra, E. Westbroek, J. Loya, L. Mitchell, S. Chang, G. Steinberg, S. Plevritis, S. Cheshier, J. Xu, S. Napel, G. Zaharchuk, G. Harsh, D. Gutman, C. Holder, R. Colen, W. Dunn, R. Jain, L. Cooper, S. Hwang, A. Flanders, D. Brat, J. Hayes, A. Droop, H. Thygesen, M. Boissinot, D. Westhead, S. Short, S. Lawler, P. Bady, S. Kurscheid, M. Delorenzi, M. E. Hegi, C. Crosby, C. Faulkner, T. Smye-Rumsby, K. Kurian, M. Williams, K. Hopkins, A. Palmer, H. Williams, C. Wragg, H. R. Haynes, K. M. Kurian, P. White, T. Oka, L. Jalbert, A. Elkhaled, R. Jensen, K. Salzman, M. Schabel, D. Gillespie, M. Mumert, B. Johnson, T. Mazor, M. Barnes, S. Yamamoto, H. Ueda, K. Tatsuno, K. Aihara, A. Bollen, M. Hirst, M. Marra, A. Mukasa, N. Saito, H. Aburatani, M. Berger, B. Taylor, S. Popov, A. Mackay, W. Ingram, A. Burford, A. Jury, M. Vinci, C. Jones, D. T. W. Jones, V. Hovestadt, S. Picelli, W. Wang, P. A. Northcott, M. Kool, G. Reifenberger, T. Pietsch, M. Sultan, H. Lehrach, M.-L. Yaspo, A. Borkhardt, P. Landgraf, R. Eils, A. Korshunov, M. Zapatka, B. Radlwimmer, S. M. Pfister, P. Lichter, A. Joy, I. Smirnov, M. Reiser, W. Shapiro, S. Kim, B. Feuerstein, C. Jungk, S. Friauf, A. Unterberg, T. A. Juratli, J. McElroy, W. Meng, A. Huebner, K. D. Geiger, D. Krex, G. Schackert, A. Chakravarti, T. Lautenschlaeger, B. Y. Kim, W. Jiang, J. Beiko, S. Prabhu, F. DeMonte, R. Sawaya, D. Cahill, I. McCutcheon, C. Lau, L. Wang, K. Terashima, S. Yamaguchi, M. Burstein, J. Sun, T. Suzuki, R. Nishikawa, H. Nakamura, A. Natsume, S. Terasaka, H.-K. Ng, D. Muzny, R. Gibbs, D. Wheeler, X.-q. Zhang, S. Sun, K.-f. Lam, K. M. Y. Kiang, J. K. S. Pu, A. S. W. Ho, G. K. K. Leung, F. Loebel, W. T. Curry, F. G. Barker, N. Lelic, A. S. Chi, D. P. Cahill, D. Lu, J. Yin, C. Teo, K. McDonald, A. Madhankumar, C. Weston, B. Slagle-Webb, J. Sheehan, A. Patel, M. Glantz, J. Connor, C. Maire, J. Francis, C.-Z. Zhang, J. Jung, V. Manzo, V. Adalsteinsson, H. Homer, B. Blumenstiel, C. S. Pedamallu, E. Nickerson, A. Ligon, C. Love, M. Meyerson, K. Ligon, L. E. Jalbert, S. J. Nelson, A. W. Bollen, I. V. Smirnov, J. S. Song, A. B. Olshen, M. S. Berger, S. M. Chang, B. S. Taylor, J. F. Costello, S. Mehta, B. Armstrong, S. Peng, A. Bapat, M. Berens, B. Melendez, M. Mollejo, P. Mur, T. Hernandez-Iglesias, C. Fiano, J. Ruiz, J. A. Rey, V. Stadler, A. Schulte, K. Lamszus, C. Schichor, M. Westphal, J.-C. Tonn, O. Morozova, S. Katzman, M. Grifford, S. Salama, D. Haussler, A. Olshen, S. Fouse, S. Nakamizo, T. Sasayama, H. Tanaka, K. Tanaka, K. Mizukawa, M. Yoshida, E. Kohmura, P. Northcott, D. Jones, S. Pfister, R. Otani, S. Takayanagi, K. Saito, S. Tanaka, M. Shin, T. Ozawa, M. Riester, Y.-K. Cheng, J. Huse, K. Helmy, N. Charles, M. Squatrito, F. Michor, E. Holland, M. Perrech, L. Dreher, G. Rohn, R. Goldbrunner, M. Timmer, B. Pollo, V. Palumbo, C. Calatozzolo, M. Patane, R. Nunziata, M. Farinotti, A. Silvani, S. Lodrini, G. Finocchiaro, E. Lopez, A. Rioscovian, R. Ruiz, G. Siordia, A. P. de Leon, C. Rostomily, R. Rostomily, D. Silbergeld, D. Kolstoe, M. Chamberlain, J. Silber, P. Roth, A. Keller, J. Hoheisel, P. Codo, A. Bauer, C. Backes, P. Leidinger, E. Meese, E. Thiel, A. Korfel, M. Weller, G. Nagae, M. Nagane, J. Z. Sanborn, T. Mikkelsen, S. Jhanwar, L. Chin, M. Nishihara, M. Schliesser, C. Grimm, E. Weiss, R. Claus, D. Weichenhan, M. Weiler, T. Hielscher, F. Sahm, B. Wiestler, A.-C. Klein, J. Blaes, C. Plass, W. Wick, G. Stragliotto, A. Rahbar, C. Soderberg-Naucler, M. Won, R. Ezhilarasan, P. Sun, D. Blumenthal, M. Vogelbaum, R. Jenkins, R. Jeraj, P. Brown, K. Jaeckle, D. Schiff, J. Dignam, J. Atkins, D. Brachman, M. Werner-Wasik, M. Mehta, J. Shen, J. Luan, A. Yu, M. Matsutani, Y. Liang, T.-K. Man, A. Trister, M. Tokita, S. Mikheeva, A. Mikheev, S. Friend, M. van den Bent, L. Erdem, T. Gorlia, M. Taphoorn, J. Kros, P. Wesseling, H. Dubbink, A. Ibdaih, P. French, H. van Thuijl, J. Heimans, B. Ylstra, J. Reijneveld, A. Prabowo, I. Scheinin, H. van Essen, W. Spliet, C. Ferrier, P. van Rijen, T. Veersema, M. Thom, A. S.-v. Meeteren, E. Aronica, H. Kim, S. Zheng, D. J. Brat, S. Virk, S. Amini, C. Sougnez, J. Barnholtz-Sloan, R. G. W. Verhaak, C. Watts, A. Sottoriva, I. Spiteri, S. Piccirillo, A. Touloumis, P. Collins, J. Marioni, C. Curtis, S. Tavare, B. Tews, T. P. C. Yeung, B. Al-Khazraji, L. Morrison, L. Hoffman, D. Jackson, T.-Y. Lee, S. Yartsev, G. Bauman, J. Fu, R. Vegesna, Y. Mao, L. E. Heathcock, W. Torres-Garcia, S. Wang, A. McKenna, C. W. Brennan, W. K. A. Yung, J. N. Weinstein, E. P. Sulman, and D. Koul
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Abstracts ,Cancer Research ,Text mining ,Oncology ,business.industry ,Neurology (clinical) ,Computational biology ,Biology ,Omics ,business - Published
- 2013
4. Gut microbiota signatures associate with prostate cancer risk
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P.J. Boström, S. Kalinen, T. Kallonen, M. Gunell, I. Jambor, P. Taimen, M. Poutanen, A. Hakanen, and E. Munukka
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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5. Damage Coupled Viscoplastic Modeling of Particulate Composites With Imperfect Interphase
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Shihua Nie, Cemal Basaran, and Eray M. Gunel
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Condensed Matter::Soft Condensed Matter ,Physics::Fluid Dynamics ,Materials science ,Viscoplasticity ,Agglomerate ,Composite number ,Constitutive equation ,Micromechanics ,Interphase ,Composite material ,Thermal expansion ,Finite element method - Abstract
A micromechanical damage model is proposed to predict the overall viscoplastic behavior and damage evolution in particulate polymer composites with imperfect interfacial bonds. The constituents are treated as three distinct phases, consisting of agglomerate of particles, bulk matrix, and interfacial transition zone around the agglomerate. The influence of the interfacial transition zone on the overall mechanical behavior of composites is studied analytically and experimentally. Test data on particle-filled acrylic composites with three different interfacial properties are presented. The coefficient of thermal expansion (CTE) mismatch between the matrix and the filler particles is also introduced into the model. A damage evolution function based on irreversible thermodynamics is also introduced into the constitutive model to describe the degradation of the composite. The efficient general return-mapping algorithm is exploited to implement the proposed unified damage-coupled viscoplastic model into finite element formulation. Furthermore, the model predictions for uniaxial loading conditions are compared with the experimental data. Both the experimental results and analytical prediction show that interfacial conditions have great influence on the elastic properties of particle-filled acrylic composites. Keywords: micromechanics; particulate composite; interfaces; interfacial bond; damage
- Published
- 2012
6. Stress Whitening Quantification of Thermoformed Mineral Filled Acrylics
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C. Basaran and E. M. Gunel
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Materials science ,Mechanical Engineering ,Stress-whitening ,Plasticity ,Condensed Matter Physics ,law.invention ,Stress (mechanics) ,chemistry.chemical_compound ,Optical microscope ,chemistry ,Mechanics of Materials ,law ,Particle ,General Materials Science ,Methyl methacrylate ,Deformation (engineering) ,Composite material ,Thermoforming - Abstract
Stress whitening problem in thermoformed alumina trihydrate (ATH) reinforced poly(methyl methacrylate) (PMMA) was studied. In situ heavy-gage thermoforming of acrylics was entirely replicated under laboratory controlled conditions at different operation parameters. Samples were monitored with optical microscope after the completion of the thermoforming operation. For stress whitening quantification, a new index was proposed from image histograms of processed optical micrographs. Results indicated that stress whitening in PMMA/ATH samples increases with level of plastic deformation at all thermoforming conditions. The influence of the forming rate and forming temperature on the degree of stress whitening was explained in terms of change in material behavior and microdeformation mechanisms around two characteristic temperatures of PMMA/ATH. Developed method for stress whitening quantification characterizes different levels of stress whitening with single numeric values. It is shown that stress whitening index and density of microdeformation features display a strong correlation. Higher density of particle cracks at low forming temperatures results in higher stress whitening levels. Increased surface irregularity and large size voids at high forming temperatures produce lower stress whitening.
- Published
- 2010
7. Azoospermia and cryptorchidism in a male with a de novo reciprocal t(Y;16) translocation
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M, Gunel, S, Cavkaytar, G, Ceylaner, and S, Batioglu
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Adult ,Male ,Chromosomes, Human, Y ,Karyotyping ,Cryptorchidism ,Humans ,Chromosome Breakage ,Chromosomes, Human, Pair 16 ,Infertility, Male ,Sex Chromosome Aberrations ,Translocation, Genetic ,Azoospermia - Abstract
An apparently balanced reciprocal translocation between the long arm of the Y chromosome and the long arm of the chromosome 16 t(Y;16)(q12;q13) is described in an infertile man with azoospermia and cryptorchidism. The patient was phenotypically normal and had bilateral inguinal hernia repair with orchidopexy at the age of 8 years. Histological examination of testicular biopsies revealed maturation arrest. Y/autosome translocations in the literature are relatively rare and mostly associated with infertility. To our knowledge, this is the sixth report about the reciprocal t(Y;16) translocation in the literature but the first presenting with cryptorchidism.
- Published
- 2008
8. Carotid endarterectomy prevention strategies and complications management
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M, Gunel and I A, Awad
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Male ,Endarterectomy, Carotid ,Postoperative Complications ,Risk Factors ,Humans ,Female ,Intraoperative Complications - Abstract
Perioperative complications of carotid endarterectomy (CEA) are uncommon but potentially devastating. The authors review strategies aimed at minimizing morbidity of surgical treatment of carotid occlusive disease. Multiple components of the perioperative course of patients who undergo CEA must be tightly controlled to maintain an acceptably low complication rate. These factors comprise appropriate patient selection, including careful assessment of techniques aimed at prevention and monitoring of intraoperative complications and postoperative care.
- Published
- 2000
9. Whole Genome Association of Intracranial Aneurysm Identifies Susceptibilty Loci
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M. Vinall and M. Gunel
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Genetics ,Aneurysm ,Association (object-oriented programming) ,medicine ,Biology ,medicine.disease ,Genome - Published
- 2009
10. Management of low-grade gliomas: radiation therapy at time of recurrence
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J M, Piepmeier and M, Gunel
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Treatment Outcome ,Brain Neoplasms ,Recurrence ,Humans ,Glioma - Published
- 1995
11. Effects of home exercise program on motor development of children with cerebral palsy: a retrospective study
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A. Livanelogliu, E. Aki, and M. Gunel
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medicine.medical_specialty ,business.industry ,Home exercise program ,Pediatrics, Perinatology and Child Health ,medicine ,Physical therapy ,Retrospective cohort study ,Neurology (clinical) ,General Medicine ,medicine.disease ,business ,Motor skill ,Cerebral palsy - Published
- 2008
12. CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow.
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Kim AH, Sakin I, Viviano S, Tuncel G, Aguilera SM, Goles G, Jeffries L, Ji W, Lakhani SA, Kose CC, Silan F, Oner SS, Kaplan OI, Ergoren MC, Mishra-Gorur K, Gunel M, Sag SO, Temel SG, and Deniz E
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- Humans, Animals, Male, Female, Fibroblasts metabolism, Mutation, Kidney metabolism, Brain metabolism, Pedigree, Xenopus, Cerebrospinal Fluid metabolism, Intellectual Disability genetics, Cilia metabolism, Ciliopathies genetics, Ciliopathies metabolism
- Abstract
Intellectual and developmental disabilities result from abnormal nervous system development. Over a 1,000 genes have been associated with intellectual and developmental disabilities, driving continued efforts toward dissecting variant functionality to enhance our understanding of the disease mechanism. This report identified two novel variants in CC2D1A in a cohort of four patients from two unrelated families. We used multiple model systems for functional analysis, including Xenopus , Drosophila , and patient-derived fibroblasts. Our experiments revealed that cc2d1a is expressed explicitly in a spectrum of ciliated tissues, including the left-right organizer, epidermis, pronephric duct, nephrostomes, and ventricular zone of the brain. In line with this expression pattern, loss of cc2d1a led to cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation via defective ciliogenesis. Interestingly, when we analyzed brain development, mutant tadpoles showed abnormal CSF circulation only in the midbrain region, suggesting abnormal local CSF flow. Furthermore, our analysis of the patient-derived fibroblasts confirmed defective ciliogenesis, further supporting our observations. In summary, we revealed novel insight into the role of CC2D1A by establishing its new critical role in ciliogenesis and CSF circulation., (© 2024 Kim et al.)
- Published
- 2024
- Full Text
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13. Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.
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Mishra-Gorur K, Barak T, Kaulen LD, Henegariu O, Jin SC, Aguilera SM, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, Rai DK, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Encicek AG, Bilguvar K, Lifton RP, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, and Gunel M
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- Humans, Virulence, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Germ-Line Mutation, Heart Defects, Congenital genetics
- Abstract
Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
- Full Text
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14. APOE ε4 and Intracerebral Hemorrhage in Patients With Brain Arteriovenous Malformation.
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Renedo D, Rivier CA, Koo AB, Sujijantarat N, Clocchiatti-Tuozzo S, Wu K, Torres-Lopez VM, Huo S, Gunel M, de Havenon A, Sheth KN, Matouk CC, and Falcone GJ
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- Female, Humans, Male, Middle Aged, Brain blood supply, Cerebral Amyloid Angiopathy complications, Cross-Sectional Studies, Apolipoprotein E4 genetics, Cerebral Hemorrhage etiology, Cerebral Hemorrhage genetics, Intracranial Arteriovenous Malformations complications
- Abstract
Importance: Intracerebral hemorrhage (ICH) is a serious complication of brain arteriovenous malformation (AVM). Apolipoprotein E (APOE) ε4 is a well-known genetic risk factor for ICH among persons without AVM, and cerebral amyloid angiopathy is a vasculopathy frequently observed in APOE ε4 carriers that may increase the risk of ICH., Objective: To assess whether APOE ε4 is associated with a higher risk of ICH in patients with a known AVM., Design, Setting, and Participants: This cross-sectional study including 412 participants was conducted in 2 stages (discovery and replication) using individual-level data from the UK Biobank (released March 2012 and last updated October 2023) and the All of Us Research Program (commenced on May 6, 2018, with its latest update provided in October 2023). The occurrence of AVM and ICH was ascertained at the time of enrollment using validated International Classification of Diseases, Ninth Revision and Tenth Revision, codes. Genotypic data on the APOE variants rs429358 and rs7412 were used to ascertain the ε status., Main Outcomes and Measures: For each study, the association between APOE ε4 variants and ICH risk was assessed among patients with a known AVM by using multivariable logistic regression., Results: The discovery phase included 253 UK Biobank participants with known AVM (mean [SD] age, 56.6 [8.0] years, 119 [47.0%] female), of whom 63 (24.9%) sustained an ICH. In the multivariable analysis of 240 participants of European ancestry, APOE ε4 was associated with a higher risk of ICH (odds ratio, 4.58; 95% CI, 2.13-10.34; P < .001). The replication phase included 159 participants with known AVM enrolled in All of Us (mean [SD] age, 57.1 [15.9] years; 106 [66.7%] female), of whom 29 (18.2%) sustained an ICH. In multivariable analysis of 101 participants of European ancestry, APOE ε4 was associated with higher risk of ICH (odds ratio, 4.52; 95% CI, 1.18-19.38; P = .03)., Conclusions and Relevance: The results of this cross-sectional study of patients from the UK Biobank and All of Us suggest that information on APOE ε4 status may help identify patients with brain AVM who are at particularly high risk of ICH and that cerebral amyloid angiopathy should be evaluated as a possible mediating mechanism of the observed association.
- Published
- 2024
- Full Text
- View/download PDF
15. Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
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Zhao S, Mekbib KY, van der Ent MA, Allington G, Prendergast A, Chau JE, Smith H, Shohfi J, Ocken J, Duran D, Furey CG, Hao LT, Duy PQ, Reeves BC, Zhang J, Nelson-Williams C, Chen D, Li B, Nottoli T, Bai S, Rolle M, Zeng X, Dong W, Fu PY, Wang YC, Mane S, Piwowarczyk P, Fehnel KP, See AP, Iskandar BJ, Aagaard-Kienitz B, Moyer QJ, Dennis E, Kiziltug E, Kundishora AJ, DeSpenza T Jr, Greenberg ABW, Kidanemariam SM, Hale AT, Johnston JM, Jackson EM, Storm PB, Lang SS, Butler WE, Carter BS, Chapman P, Stapleton CJ, Patel AB, Rodesch G, Smajda S, Berenstein A, Barak T, Erson-Omay EZ, Zhao H, Moreno-De-Luca A, Proctor MR, Smith ER, Orbach DB, Alper SL, Nicoli S, Boggon TJ, Lifton RP, Gunel M, King PD, Jin SC, and Kahle KT
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- Humans, Animals, Mice, Endothelial Cells pathology, Mutation, Signal Transduction genetics, Mutation, Missense, GTPase-Activating Proteins genetics, Activin Receptors, Type II genetics, p120 GTPase Activating Protein genetics, Vein of Galen Malformations genetics, Vein of Galen Malformations pathology, Vascular Diseases
- Abstract
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10
-7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5 ), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families., (© 2023. The Author(s).)- Published
- 2023
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16. Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.
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Khoshkhoo S, Wang Y, Chahine Y, Erson-Omay EZ, Robert SM, Kiziltug E, Damisah EC, Nelson-Williams C, Zhu G, Kong W, Huang AY, Stronge E, Phillips HW, Chhouk BH, Bizzotto S, Chen MH, Adikari TN, Ye Z, Witkowski T, Lai D, Lee N, Lokan J, Scheffer IE, Berkovic SF, Haider S, Hildebrand MS, Yang E, Gunel M, Lifton RP, Richardson RM, Blümcke I, Alexandrescu S, Huttner A, Heinzen EL, Zhu J, Poduri A, DeLanerolle N, Spencer DD, Lee EA, Walsh CA, and Kahle KT
- Subjects
- Humans, Female, Adult, Middle Aged, Male, Mitogen-Activated Protein Kinases metabolism, Retrospective Studies, Hippocampus pathology, Epilepsy, Temporal Lobe surgery, Epilepsy pathology, Drug Resistant Epilepsy, Neocortex
- Abstract
Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown., Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE., Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022., Exposures: Drug-resistant MTLE., Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex., Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism., Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.
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- 2023
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17. Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas.
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Tabor JK, O'Brien J, Vasandani S, Vetsa S, Lei H, Jalal MI, Marianayagam NJ, Jin L, Millares Chavez M, Haynes J, Dincer A, Yalcin K, Aguilera SM, Omay SB, Mishra-Gorur K, McGuone D, Morales-Valero SF, Fulbright RK, Gunel M, Erson-Omay EZ, and Moliterno J
- Subjects
- Humans, Mutation genetics, Genomics, Meningioma genetics, Meningioma surgery, Meningioma complications, Meningeal Neoplasms genetics, Meningeal Neoplasms surgery, Meningeal Neoplasms complications, Supratentorial Neoplasms genetics, Supratentorial Neoplasms surgery
- Abstract
Objective: Mutations in NF2 are the most common somatic driver mutation in sporadic meningiomas. NF2 mutant meningiomas preferentially arise along the cerebral convexities-however, they can also be found in the posterior fossa. The authors investigated whether NF2 mutant meningiomas differ in clinical and genomic features based on their location relative to the tentorium., Methods: Clinical and whole exome sequencing (WES) data for patients who underwent resection of sporadic NF2 mutant meningiomas were reviewed and analyzed., Results: A total of 191 NF2 mutant meningiomas were included (165 supratentorial, 26 infratentorial). Supratentorial NF2 mutant meningiomas were significantly associated with edema (64.0% vs 28.0%, p < 0.001); higher grade-i.e., WHO grade II or III (41.8% vs 3.9%, p < 0.001); elevated Ki-67 (55.0% vs 13.6%, p < 0.001); and larger volume (mean 45.5 cm3 vs 14.9 cm3, p < 0.001). Furthermore, supratentorial tumors were more likely to harbor the higher-risk feature of chromosome 1p deletion (p = 0.038) and had a larger fraction of the genome altered with loss of heterozygosity (p < 0.001). Infratentorial meningiomas were more likely to undergo subtotal resection than supratentorial tumors (37.5% vs 15.8%, p = 0.021); however, there was no significant difference in overall (p = 0.2) or progression-free (p = 0.4) survival., Conclusions: Supratentorial NF2 mutant meningiomas are associated with more aggressive clinical and genomic features as compared with their infratentorial counterparts. Although infratentorial tumors have higher rates of subtotal resection, there is no associated difference in survival or recurrence. These findings help to better inform surgical decision-making in the management of NF2 mutant meningiomas based on location, and may guide postoperative management of these tumors.
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- 2023
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18. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
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Mishra-Gorur K, Barak T, Kaulen LD, Henegariu O, Jin SC, Aguilera SM, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, Rai DK, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Sencicek AG, Bilguvar K, Lifton RP, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, and Gunel M
- Subjects
- Animals, Adaptor Proteins, Signal Transducing metabolism, Mutation, Skull metabolism, Zebrafish genetics, Zebrafish metabolism, Zebrafish Proteins genetics, Humans, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Heart Defects, Congenital genetics, Meningeal Neoplasms genetics, Meningioma genetics, Meningioma pathology
- Abstract
While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7- expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7 -mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7 -driven meningiomas and developmental heart defects.
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- 2023
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19. Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations.
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Zhao S, Mekbib KY, van der Ent MA, Allington G, Prendergast A, Chau JE, Smith H, Shohfi J, Ocken J, Duran D, Furey CG, Le HT, Duy PQ, Reeves BC, Zhang J, Nelson-Williams C, Chen D, Li B, Nottoli T, Bai S, Rolle M, Zeng X, Dong W, Fu PY, Wang YC, Mane S, Piwowarczyk P, Fehnel KP, See AP, Iskandar BJ, Aagaard-Kienitz B, Kundishora AJ, DeSpenza T, Greenberg ABW, Kidanemariam SM, Hale AT, Johnston JM, Jackson EM, Storm PB, Lang SS, Butler WE, Carter BS, Chapman P, Stapleton CJ, Patel AB, Rodesch G, Smajda S, Berenstein A, Barak T, Erson-Omay EZ, Zhao H, Moreno-De-Luca A, Proctor MR, Smith ER, Orbach DB, Alper SL, Nicoli S, Boggon TJ, Lifton RP, Gunel M, King PD, Jin SC, and Kahle KT
- Abstract
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10
-7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10-5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.- Published
- 2023
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20. Vascular steal and associated intratumoral aneurysms in highly vascular brain tumors: illustrative case.
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Hong CS, Marianayagam NJ, Morales-Valero SF, Barak T, Tabor JK, O'Brien J, Huttner A, Baehring J, Gunel M, Erson-Omay EZ, Fulbright RK, Matouk CC, and Moliterno J
- Abstract
Background: Intratumoral aneurysms in highly vascular brain tumors can complicate resection depending on their location and feasibility of proximal control. Seemingly unrelated neurological symptoms may be from vascular steal that can help alert the need for additional vascular imaging and augmenting surgical strategies., Observations: A 29-year-old female presented with headaches and unilateral blurred vision, secondary to a large right frontal dural-based lesion with hypointense signal thought to represent calcifications. Given these latter findings and clinical suspicion for a vascular steal phenomenon to explain the blurred vision, computed tomography angiography was obtained, revealing a 4 × 2-mm intratumoral aneurysm. Diagnostic cerebral angiography confirmed this along with vascular steal by the tumor from the right ophthalmic artery. The patient underwent endovascular embolization of the intratumoral aneurysm, followed by open tumor resection in the same setting without complication, minimal blood loss, and improvement in her vision., Lessons: Understanding the blood supply of any tumor, but highly vascular ones in particular, and the relationship with normal vasculature is undeniably important in avoiding potentially dangerous situations and optimizing maximal safe resection. Recognition of highly vascular tumors should prompt thorough understanding of the vascular supply and relationship of intracranial vasculature with consideration of endovascular adjuncts when appropriate.
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- 2023
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21. Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts.
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Kundishora AJ, Allington G, McGee S, Mekbib KY, Gainullin V, Timberlake AT, Nelson-Williams C, Kiziltug E, Smith H, Ocken J, Shohfi J, Allocco A, Duy PQ, Elsamadicy AA, Dong W, Zhao S, Wang YC, Qureshi HM, DiLuna ML, Mane S, Tikhonova IR, Fu PY, Castaldi C, López-Giráldez F, Knight JR, Furey CG, Carter BS, Haider S, Moreno-De-Luca A, Alper SL, Gunel M, Millan F, Lifton RP, Torene RI, Jin SC, and Kahle KT
- Subjects
- Humans, Animals, Mice, Brain diagnostic imaging, Exome genetics, Genetic Testing, Multiomics, Arachnoid Cysts diagnostic imaging, Arachnoid Cysts genetics
- Abstract
Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10
-33 ). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2023
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22. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.
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Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, Marlier A, Allington G, Greenberg ABW, DeSpenza T Jr, Singh AK, Zeng X, Mekbib KY, Kundishora AJ, Nelson-Williams C, Hao LT, Zhang J, Lam TT, Wilson R, Butler WE, Diluna ML, Feinberg P, Schafer DP, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick DD Jr, Schiff SJ, Carter BS, Gunel M, Simard JM, Lifton RP, Alper SL, Delpire E, and Kahle KT
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- Humans, Blood-Brain Barrier metabolism, Brain metabolism, Immunity, Innate, Cytokine Release Syndrome pathology, Choroid Plexus metabolism, Hydrocephalus cerebrospinal fluid, Hydrocephalus immunology
- Abstract
The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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23. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.
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Cali E, Suri M, Scala M, Ferla MP, Alavi S, Faqeih EA, Bijlsma EK, Wigby KM, Baralle D, Mehrjardi MYV, Schwab J, Platzer K, Steindl K, Hashem M, Jones M, Niyazov DM, Jacober J, Littlejohn RO, Weis D, Zadeh N, Rodan L, Goldenberg A, Lecoquierre F, Dutra-Clarke M, Horvath G, Young D, Orenstein N, Bawazeer S, Vulto-van Silfhout AT, Herenger Y, Dehghani M, Seyedhassani SM, Bahreini A, Nasab ME, Ercan-Sencicek AG, Firoozfar Z, Movahedinia M, Efthymiou S, Striano P, Karimiani EG, Salpietro V, Taylor JC, Redman M, Stegmann APA, Laner A, Abdel-Salam G, Li M, Bengala M, Müller AJ, Digilio MC, Rauch A, Gunel M, Titheradge H, Schweitzer DN, Kraus A, Valenzuela I, McLean SD, Phornphutkul C, Salih M, Begtrup A, Schnur RE, Torti E, Haack TB, Prada CE, Alkuraya FS, Houlden H, and Maroofian R
- Subjects
- Humans, Obesity genetics, Phenotype, Protein-Arginine N-Methyltransferases genetics, Brachydactyly, Neurodevelopmental Disorders genetics, Intellectual Disability genetics, Dwarfism genetics, Musculoskeletal Abnormalities
- Abstract
Purpose: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder., Methods: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature., Results: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss., Conclusion: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities., Competing Interests: Conflict of Interest Megan Li is an employee of Invitae. Erin Torti, Amber Begtrup, and Rhonda E Schnur are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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24. Biallelic BICD2 variant is a novel candidate for Cohen-like syndrome.
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Caglayan AO, Tuysuz B, Gül E, Alkaya DU, Yalcinkaya C, Gleeson JG, Bilguvar K, and Gunel M
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- Genes, Dominant, Humans, Microtubule-Associated Proteins genetics, Mutation, Mutation, Missense, Intellectual Disability genetics, Muscular Atrophy, Spinal genetics
- Abstract
Heterozygous mutations in Bicaudal D2 Drosophila homolog 2 (BICD2) gene, encodes a vesicle transport protein involved in dynein-mediated movement along microtubules, are responsible for an exceedingly rare autosomal dominant spinal muscular atrophy type 2A which starts in the childhood and predominantly effects lower extremities. Recently, a more severe form, type 2B, has also been described. Here, we present a patient born to a consanguineous union and who suffered from intellectual disability, speech delay, epilepsy, happy facial expression, truncal obesity with tappering fingers, and joint hypermobility. Whole-exome sequencing analysis revealed a rare, homozygous missense mutation (c.731T>C; p.Leu244Pro) in BICD2 gene. This finding presents the first report in the literature for homozygous BICD2 mutations and its association with a Cohen-Like syndrome. Patients presenting with Cohen-Like phenotypes should be further interrogated for mutations in BICD2., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)
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- 2022
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25. Mutation spectrum of congenital heart disease in a consanguineous Turkish population.
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Dong W, Kaymakcalan H, Jin SC, Diab NS, Tanıdır C, Yalcin ASY, Ercan-Sencicek AG, Mane S, Gunel M, Lifton RP, Bilguvar K, and Brueckner M
- Subjects
- Consanguinity, Humans, Mutation, Turkey, Exome Sequencing, Heart Defects, Congenital genetics
- Abstract
Backgrounds: While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts., Methods: We recruited 73 CHD probands from consanguineous families in Turkey and used whole-exome sequencing (WES) to identify genetic lesions in these patients., Results: On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss-of-function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D-TGA). Three additional patients (4.1%) harbored other types of CHD-associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity., Conclusions: Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2022
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26. Genetically Determined Low-Density Lipoprotein Cholesterol and Risk of Subarachnoid Hemorrhage.
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Acosta JN, Both CP, Szejko N, Leasure AC, Abdelhakim S, Torres-Lopez VM, Brown SC, Matouk CC, Gunel M, Sheth KN, and Falcone GJ
- Subjects
- Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Cholesterol, LDL blood, Cholesterol, LDL genetics, Subarachnoid Hemorrhage blood, Subarachnoid Hemorrhage genetics
- Abstract
We evaluated whether genetically elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with lower risk of intracranial aneurysms and subarachnoid hemorrhage (IA/SAH). We conducted a 2-sample Mendelian randomization (MR) study. Our primary analysis used the inverse-variance weighted method. In secondary analyses, we implemented the MR-PRESSO method, restricted our analysis to LDL-C-specific instruments, and performed multivariate MR. A 1-mmol/l increase in genetically instrumented LDL-C levels was associated with a 17% lower risk of IA/SAH (odds ratio = 0.83, 95% confidence interval = 0.73-0.94, p = 0.004). Results remained consistent in secondary and multivariate analyses (all p < 0.05). Our results provide evidence for an inverse causal relationship between LDL-C levels and risk of IA/SAH. ANN NEUROL 2022;91:145-149., (© 2021 American Neurological Association.)
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- 2022
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27. Targeting the CSF1/CSF1R axis is a potential treatment strategy for malignant meningiomas.
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Yeung J, Yaghoobi V, Miyagishima D, Vesely MD, Zhang T, Badri T, Nassar A, Han X, Sanmamed MF, Youngblood M, Peyre M, Kalamarides M, Rimm DL, Gunel M, and Chen L
- Subjects
- Animals, Humans, Macrophages, Mice, Tumor Microenvironment, Macrophage Colony-Stimulating Factor, Meningeal Neoplasms drug therapy, Meningioma drug therapy, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
- Abstract
Background: Malignant meningiomas are fatal and lack effective therapy. As M2 macrophages are the most prevalent immune cell type in human meningiomas, we hypothesized that normalizing this immunosuppressive population would be an effective treatment strategy., Methods: We used CIBERSORTx to examine the proportions of 22 immune subsets in human meningiomas. We targeted the colony-stimulating factor 1 (CSF1) or CSF1 receptor (CSF1R) axis, an important regulator of macrophage phenotype, using monoclonal antibodies (mAbs) in a novel immunocompetent murine model (MGS1) for malignant meningioma. RNA sequencing (RNA-seq) was performed to identify changes in gene expression in the tumor microenvironment (TME). Mass cytometry was used to delineate changes in immune subsets after treatment. We measured patients' plasma CSF1 levels using ELISA and CSF1R expression using multiplex quantitative immunofluorescence in a human meningioma tissue microarray., Results: Human meningiomas are heavily enriched for immunosuppressive myeloid cells. MGS1 recapitulates the TME of human meningiomas, including an abundance of myeloid cells, a paucity of infiltrating T cells, and low programmed death ligand 1 (PD-L1) expression. Treatment of murine meningiomas with anti-CSF1/CSF1R, but not programmed cell death receptor 1 (PD-1), mAbs abrogate tumor growth. RNA-seq and mass cytometry analyses reveal a myeloid cell reprogramming with limited effect on T cells in the TME. CSF1 plasma levels are significantly elevated in human patients, and CSF1R is highly expressed on CD163+ macrophages within the human TME., Conclusion: Our findings suggest that anti-CSF1/CSF1R antibody treatment may be an effective normalization cancer immunotherapy for malignant meningiomas., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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28. Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.
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Jin L, Youngblood MW, Gupte TP, Vetsa S, Nadar A, Barak T, Yalcin K, Aguilera SM, Mishra-Gorur K, Blondin NA, Gorelick E, Omay SB, Pointdujour-Lim R, Judson BL, Alperovich M, Aboian MS, McGuone D, Gunel M, Erson-Omay Z, Fulbright RK, and Moliterno J
- Subjects
- Genomics, Humans, Treatment Outcome, Hyperostosis diagnostic imaging, Hyperostosis genetics, Meningeal Neoplasms diagnostic imaging, Meningeal Neoplasms genetics, Meningioma diagnostic imaging, Meningioma genetics
- Abstract
Purpose: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature., Methods: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features., Results: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004)., Conclusions: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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29. DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.
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Kundishora AJ, Peters ST, Pinard A, Duran D, Panchagnula S, Barak T, Miyagishima DF, Dong W, Smith H, Ocken J, Dunbar A, Nelson-Williams C, Haider S, Walker RL, Li B, Zhao H, Thumkeo D, Marlier A, Duy PQ, Diab NS, Reeves BC, Robert SM, Sujijantarat N, Stratman AN, Chen YH, Zhao S, Roszko I, Lu Q, Zhang B, Mane S, Castaldi C, López-Giráldez F, Knight JR, Bamshad MJ, Nickerson DA, Geschwind DH, Chen SL, Storm PB, Diluna ML, Matouk CC, Orbach DB, Alper SL, Smith ER, Lifton RP, Gunel M, Milewicz DM, Jin SC, and Kahle KT
- Subjects
- Adult, Age of Onset, Cell Adhesion Molecules genetics, Child, Child, Preschool, Cohort Studies, Computer Simulation, Exome genetics, Female, Genetic Variation, Humans, Infant, Magnetic Resonance Imaging, Male, Middle Aged, Moyamoya Disease diagnostic imaging, Phenotype, Sequence Analysis, RNA, White People, Exome Sequencing, Formins genetics, Moyamoya Disease genetics
- Abstract
Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals., Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk., Design, Setting, and Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort., Main Outcomes and Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue., Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways., Conclusions and Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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- 2021
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30. Clinical characteristics and outcomes for 7,995 patients with SARS-CoV-2 infection.
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McPadden J, Warner F, Young HP, Hurley NC, Pulk RA, Singh A, Durant TJS, Gong G, Desai N, Haimovich A, Taylor RA, Gunel M, Dela Cruz CS, Farhadian SF, Siner J, Villanueva M, Churchwell K, Hsiao A, Torre CJ Jr, Velazquez EJ, Herbst RS, Iwasaki A, Ko AI, Mortazavi BJ, Krumholz HM, and Schulz WL
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, COVID-19 diagnosis, COVID-19 mortality, COVID-19 therapy, COVID-19 Testing, Cohort Studies, Female, Hospital Mortality, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Treatment Outcome, Young Adult, COVID-19 epidemiology
- Abstract
Objective: Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2., Design: This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository., Setting: Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas., Populations: The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020., Main Outcome and Performance Measures: Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support., Results: Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 2152 (99.9%) had a discharge disposition at the end of the study period. Of these, 329 (15.3%) required invasive mechanical ventilation and 305 (14.2%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 80.7 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups., Conclusions: This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines., Competing Interests: H.M.K. works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs; was a recipient of a research grant, through Yale, from Medtronic and the U.S. Food and Drug Administration to develop methods for post-market surveillance of medical devices; was a recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Martin Baughman Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a member of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; and is the co-founder of HugoHealth, a personal health information platform, and cofounder of Refactor Health, a healthcare AI-augmented data management company. W.L.S. was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to HugoHealth, a personal health information platform, and cofounder of Refactor Health, an AI-augmented data management platform for healthcare; is a consultant for Interpace Diagnostics Group, a molecular diagnostics company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.
- Published
- 2021
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31. Neuroinvasion of SARS-CoV-2 in human and mouse brain.
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Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, and Iwasaki A
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Male, Mice, Middle Aged, Organoids metabolism, Organoids pathology, Organoids virology, Angiotensin-Converting Enzyme 2 antagonists & inhibitors, Angiotensin-Converting Enzyme 2 metabolism, Antibodies, Blocking chemistry, COVID-19 metabolism, COVID-19 pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Cerebral Cortex virology, Neurons metabolism, Neurons pathology, Neurons virology, SARS-CoV-2 metabolism
- Abstract
Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2., Competing Interests: Disclosures: M. Gunel reported personal fees from AI Therapeutics outside the submitted work; and reported, "AI Therapeutics is currently sponsoring a clinical trial for a therapeutic, which has no relevance for this study, in COVID-19. I am the Chief Scientific Advisor to AI Therapeutics." C.B. Wilen reported personal fees from ZymoResearch outside the submitted work; in addition, C.B. Wilen had a patent for compounds and compositions for treating, ameliorating, and/or preventing SARS-CoV-2 infection and/or complications thereof pending. S. Haik reported a patent to Method for treating prion diseases (PCT/EP 2019/070457) pending. A. Iwasaki reported "other" from RIGImmune and grants from Spring Discovery during the conduct of the study; in addition, A. Iwasaki had a patent to 14/776,463 pending, a patent for a T cell-based immunotherapy for central nervous system viral infections and tumors pending, and a patent to manipulation of meningeal lymphatic vasculature for brain and CNS tumor therapy pending. No other disclosures were reported., (© 2021 Song et al.)
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- 2021
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32. METAP1 mutation is a novel candidate for autosomal recessive intellectual disability.
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Caglayan AO, Aktar F, Bilguvar K, Baranoski JF, Akgumus GT, Harmanci AS, Erson-Omay EZ, Yasuno K, Caksen H, and Gunel M
- Subjects
- Adolescent, Child, Female, Humans, Male, Pedigree, Siblings, Exome Sequencing, Aminopeptidases genetics, Genes, Recessive, Intellectual Disability genetics, Intellectual Disability pathology, Mutation
- Abstract
Intellectual disability (ID) is a genetic and clinically heterogeneous common disease and underlying molecular pathogenesis can frequently not be identified by whole-exome/genome testing. Here, we report four siblings born to a consanguineous union who presented with intellectual disability and discuss the METAP1 pathway as a novel etiology of ID. Genomic analyses demonstrated that patients harbor a novel homozygous nonsense mutation in the gene METAP1. METAP1 codes for methionine aminopeptidase 1 (MetAP1) which oversees the co-translational excision of the first methionine remnants in eukaryotes. The loss-of-function mutations to this gene may result in a defect in the translation of many essential proteins within a cell. Improper neuronal function resulting from this loss of essential proteins could lead to neurologic impairment and ID.
- Published
- 2021
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33. Spatially Resolved and Quantitative Analysis of the Immunological Landscape in Human Meningiomas.
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Yeung J, Yaghoobi V, Aung TN, Vesely MD, Zhang T, Gaule P, Gunel M, Rimm DL, and Chen L
- Subjects
- Biomarkers, Tumor, Humans, Lymphocytes, Tumor-Infiltrating metabolism, Macrophages metabolism, Meningeal Neoplasms pathology, B7-H1 Antigen metabolism, Meningeal Neoplasms metabolism, Meningioma metabolism, Programmed Cell Death 1 Ligand 2 Protein metabolism
- Abstract
The immunological status of human meningiomas is not well understood, hindering the development of rational immunotherapeutic strategies. We measured the levels of PD-L1, PD-L2, and immune cell subsets using multiplex quantitative immunofluorescence in a tissue microarray composed of 73 human meningiomas (56 WHO Grade 1, 13 WHO Grade 2, and 4 WHO Grade 3). We analyzed tumor-infiltrating immune cell populations, T-cell activation/dysfunction, and macrophage phenotypes. PD-L1 and PD-L2 were detected in 5.8% and 68.7% of cases, respectively. There was a higher PD-L1 expression in CD68+ macrophages compared with tumor cells (p < 0.001). There was a weak positive correlation between PD-L1 expression and CD3+ T-cell infiltration. The level of CD3+ cells and T-cell activation/proliferation in human meningiomas were highly variable with an increased CD4-to-CD8 ratio in higher grade tumors (p < 0.05). There was a stronger correlation between GZMB/Ki67 with PD-L2 than PD-L1. We found that 15.23%, 6.66%, and 5.49% of macrophages were CD163+, CD68+, and CD163+CD68+, respectively. In cases where there is high CD3+ T-cell infiltration, 23.5% and 76.5% had dormant and activated T-cell phenotypes, respectively. We conclude that human meningiomas are either PD-L1low TILlow or PD-L1low TILhigh tumors and harbor variable TIL infiltration and phenotypes., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)
- Published
- 2021
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34. Genetically Determined Smoking Behavior and Risk of Nontraumatic Subarachnoid Hemorrhage.
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Acosta JN, Szejko N, Both CP, Vanent K, Noche RB, Gill TM, Matouk CC, Sheth KN, Gunel M, and Falcone GJ
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- Adult, Aged, Databases, Factual, Electronic Health Records, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Intracranial Aneurysm complications, Male, Mendelian Randomization Analysis, Middle Aged, Multifactorial Inheritance, Odds Ratio, Risk Assessment, Self Report, Stroke etiology, Treatment Outcome, United Kingdom epidemiology, Smoking epidemiology, Smoking genetics, Subarachnoid Hemorrhage epidemiology
- Abstract
Background and Purpose: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH., Methods: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate ( P <5 ×10
- 8 ) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods., Results: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20-1.21]; P <0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03-1.17]; P =0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15-2.31]; P =0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13-2.17]; P =0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06-2.86]; P =0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P =0.39; MR Pleiotropy Residual Sum and Outlier global test P =0.69)., Conclusions: These findings provide evidence for a causal link between smoking and the risk of SAH.- Published
- 2021
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35. Clinical and genomic factors associated with seizures in meningiomas.
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Gupte TP, Li C, Jin L, Yalcin K, Youngblood MW, Miyagishima DF, Mishra-Gorur K, Zhao AY, Antonios J, Huttner A, McGuone D, Blondin NA, Contessa JN, Zhang Y, Fulbright RK, Gunel M, Erson-Omay Z, and Moliterno J
- Abstract
Objective: The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients., Methods: Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures., Results: Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis., Conclusions: Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.
- Published
- 2020
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36. Clinical Characteristics and Outcomes for 7,995 Patients with SARS-CoV-2 Infection.
- Author
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McPadden J, Warner F, Young HP, Hurley NC, Pulk RA, Singh A, Durant TJ, Gong G, Desai N, Haimovich A, Taylor RA, Gunel M, Cruz CSD, Farhadian SF, Siner J, Villanueva M, Churchwell K, Hsiao A, Torre CJ Jr, Velazquez EJ, Herbst RS, Iwasaki A, Ko AI, Mortazavi BJ, Krumholz HM, and Schulz WL
- Abstract
Objective: Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2., Design: This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository., Setting: Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas., Populations: The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020., Main Outcome and Performance Measures: Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support., Results: Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 2152 (99.9%) had a discharge disposition at the end of the study period. Of these, 329 (15.3%) required invasive mechanical ventilation and 305 (14.2%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 80.7 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups., Conclusions: This observational study identified, among people testing positive for SARSCoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines., Competing Interests: Competing Interests H.M.K. works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs; was a recipient of a research grant, through Yale, from Medtronic and the U.S. Food and Drug Administration to develop methods for post-market surveillance of medical devices; was a recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Martin Baughman Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a member of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; and is the co-founder of HugoHealth, a personal health information platform, and co-founder of Refactor Health, a healthcare AI-augmented data management company. W.L.S. was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to HugoHealth, a personal health information platform, and cofounder of Refactor Health, an AI-augmented data management platform for healthcare; is a consultant for Interpace Diagnostics Group, a molecular diagnostics company.
- Published
- 2020
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37. Neuroinvasion of SARS-CoV-2 in human and mouse brain.
- Author
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Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, and Iwasaki A
- Abstract
Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
- Published
- 2020
- Full Text
- View/download PDF
38. Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.
- Author
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Falcone GJ, Kirsch E, Acosta JN, Noche RB, Leasure A, Marini S, Chung J, Selim M, Meschia JF, Brown DL, Worrall BB, Tirschwell DL, Jagiella JM, Schmidt H, Jimenez-Conde J, Fernandez-Cadenas I, Lindgren A, Slowik A, Gill D, Holmes M, Phuah CL, Petersen NH, Matouk Md CN, Gunel M, Sansing L, Bennett D, Chen Z, Sun LL, Clarke R, Walters RG, Gill TM, Biffi A, Kathiresan S, Langefeld CD, Woo D, Rosand J, Sheth KN, and Anderson CD
- Subjects
- Aged, Aged, 80 and over, Cholesterol, HDL blood, Cholesterol, HDL genetics, Cholesterol, LDL genetics, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides blood, Triglycerides genetics, Cerebral Hemorrhage blood, Cerebral Hemorrhage genetics, Cholesterol, LDL blood, Genetic Predisposition to Disease
- Abstract
Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH., Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses., Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10
-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively., Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66., (© 2020 American Neurological Association.)- Published
- 2020
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39. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.
- Author
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Perenthaler E, Nikoncuk A, Yousefi S, Berdowski WM, Alsagob M, Capo I, van der Linde HC, van den Berg P, Jacobs EH, Putar D, Ghazvini M, Aronica E, van IJcken WFJ, de Valk WG, Medici-van den Herik E, van Slegtenhorst M, Brick L, Kozenko M, Kohler JN, Bernstein JA, Monaghan KG, Begtrup A, Torene R, Al Futaisi A, Al Murshedi F, Mani R, Al Azri F, Kamsteeg EJ, Mojarrad M, Eslahi A, Khazaei Z, Darmiyan FM, Doosti M, Karimiani EG, Vandrovcova J, Zafar F, Rana N, Kandaswamy KK, Hertecant J, Bauer P, AlMuhaizea MA, Salih MA, Aldosary M, Almass R, Al-Quait L, Qubbaj W, Coskun S, Alahmadi KO, Hamad MHA, Alwadaee S, Awartani K, Dababo AM, Almohanna F, Colak D, Dehghani M, Mehrjardi MYV, Gunel M, Ercan-Sencicek AG, Passi GR, Cheema HA, Efthymiou S, Houlden H, Bertoli-Avella AM, Brooks AS, Retterer K, Maroofian R, Kaya N, van Ham TJ, and Barakat TS
- Subjects
- Animals, Child, Preschool, Female, Humans, Infant, Male, Mutation, Pedigree, Zebrafish, Brain Diseases genetics, Epileptic Syndromes genetics, Genes, Essential genetics, UTP-Glucose-1-Phosphate Uridylyltransferase genetics
- Abstract
Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
- Published
- 2020
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40. Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3 .
- Author
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Allocco AA, Jin SC, Duy PQ, Furey CG, Zeng X, Dong W, Nelson-Williams C, Karimy JK, DeSpenza T, Hao LT, Reeves B, Haider S, Gunel M, Lifton RP, and Kahle KT
- Abstract
Background: ATP1A3 encodes the α3 subunit of the Na
+ /K+ ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, ATP1A3 is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in ATP1A3 have never been associated with any human disease. Atp1a3 deficiency in zebrafish results in hydrocephalus; however, no known association exists between ATP1A3 and human congenital hydrocephalus (CH)., Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel ATP1A3 mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize Atp1a3 expression during brain development., Results: We identified two germline mutations in ATP1A3 (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient's unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust Atp1a3 expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain., Conclusion: These data provide the first evidence of a recessive human phenotype associated with mutations in ATP1A3 , and implicate impaired Na+ /K+ ATPase function in the pathogenesis of CH., (Copyright © 2019 Allocco, Jin, Duy, Furey, Zeng, Dong, Nelson-Williams, Karimy, DeSpenza, Hao, Reeves, Haider, Gunel, Lifton and Kahle.)- Published
- 2019
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41. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive c erebellar, o cular, cranio f acial and g enital features (COFG syndrome).
- Author
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Rad A, Altunoglu U, Miller R, Maroofian R, James KN, Çağlayan AO, Najafi M, Stanley V, Boustany RM, Yeşil G, Sahebzamani A, Ercan-Sencicek G, Saeidi K, Wu K, Bauer P, Bakey Z, Gleeson JG, Hauser N, Gunel M, Kayserili H, and Schmidts M
- Subjects
- Brain abnormalities, Brain diagnostic imaging, Child, Child, Preschool, Consanguinity, Facies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Homeodomain Proteins chemistry, Homozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Models, Molecular, Pedigree, Polymorphism, Single Nucleotide, Protein Conformation, Syndrome, Exome Sequencing, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Homeodomain Proteins genetics, Loss of Function Mutation, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics, Phenotype
- Abstract
Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs., Objective: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families., Results: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly., Conclusion: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2019
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42. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.
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Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, Gaillard J, Furey CG, Lu Q, Timberlake AT, Dong W, Sorscher MA, Loring E, Klein J, Allocco A, Hunt A, Conine S, Karimy JK, Youngblood MW, Zhang J, DiLuna ML, Matouk CC, Mane S, Tikhonova IR, Castaldi C, López-Giráldez F, Knight J, Haider S, Soban M, Alper SL, Komiyama M, Ducruet AF, Zabramski JM, Dardik A, Walcott BP, Stapleton CJ, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith ER, Orbach DB, Berenstein A, Bilguvar K, Vikkula M, Gunel M, Lifton RP, and Kahle KT
- Subjects
- Ephrins metabolism, Female, Humans, Male, Membrane Glycoproteins genetics, Metalloendopeptidases genetics, Pedigree, Penetrance, Receptor, EphB4 genetics, Signal Transduction, Vein of Galen Malformations pathology, Chromatin Assembly and Disassembly genetics, Mutation, Vein of Galen Malformations genetics
- Abstract
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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43. Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.
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Guemez-Gamboa A, Çağlayan AO, Stanley V, Gregor A, Zaki MS, Saleem SN, Musaev D, McEvoy-Venneri J, Belandres D, Akizu N, Silhavy JL, Schroth J, Rosti RO, Copeland B, Lewis SM, Fang R, Issa MY, Per H, Gumus H, Bayram AK, Kumandas S, Akgumus GT, Erson-Omay EZ, Yasuno K, Bilguvar K, Heimer G, Pillar N, Shomron N, Weissglas-Volkov D, Porat Y, Einhorn Y, Gabriel S, Ben-Zeev B, Gunel M, and Gleeson JG
- Subjects
- Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Protocadherins, Brain Stem abnormalities, Cadherins genetics, Nervous System Malformations genetics, Nervous System Malformations pathology
- Abstract
Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome., Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression., Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth., Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655., (© 2018 American Neurological Association.)
- Published
- 2018
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44. De novo MYH9 mutation in congenital scalp hemangioma.
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Fomchenko EI, Duran D, Jin SC, Dong W, Erson-Omay EZ, Antwi P, Allocco A, Gaillard JR, Huttner A, Gunel M, DiLuna ML, and Kahle KT
- Subjects
- Female, Germ-Line Mutation, Hemangioma pathology, Humans, Infant, Newborn, Loss of Function Mutation, Scalp pathology, Skin Neoplasms pathology, Hemangioma genetics, Molecular Motor Proteins genetics, Myosin Heavy Chains genetics, Skin Neoplasms genetics
- Abstract
Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score of >0.99 and is highly intolerant to missense variation ( z score = 5.59). The p.(Arg1770Cys) mutation substitutes an evolutionarily conserved amino acid in the protein's critical myosin tail domain and is predicted to be highly deleterious by SIFT, PolyPhen-2, MetaSVM, and CADD. MYH9 is a known regulator of cytokinesis, VEGF-regulated angiogenesis, and p53-dependent tumorigenesis. These findings reveal a novel association of germline de novo MYH9 mutation with congenital hemangioma., (© 2018 Fomchenko et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2018
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45. Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
- Author
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Schaffer AE, Breuss MW, Caglayan AO, Al-Sanaa N, Al-Abdulwahed HY, Kaymakçalan H, Yılmaz C, Zaki MS, Rosti RO, Copeland B, Baek ST, Musaev D, Scott EC, Ben-Omran T, Kariminejad A, Kayserili H, Mojahedi F, Kara M, Cai N, Silhavy JL, Elsharif S, Fenercioglu E, Barshop BA, Kara B, Wang R, Stanley V, James KN, Nachnani R, Kalur A, Megahed H, Incecik F, Danda S, Alanay Y, Faqeih E, Melikishvili G, Mansour L, Miller I, Sukhudyan B, Chelly J, Dobyns WB, Bilguvar K, Jamra RA, Gunel M, and Gleeson JG
- Subjects
- Actin-Related Protein 2-3 Complex metabolism, Animals, Cerebral Cortex metabolism, Cerebral Cortex pathology, Embryo, Mammalian, Genome, Human, Humans, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins genetics, Neurons metabolism, Pedigree, alpha Catenin metabolism, Actin-Related Protein 2-3 Complex genetics, Cell Movement genetics, Cerebral Cortex physiology, Neurons pathology, alpha Catenin genetics
- Abstract
Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities
1 . Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.- Published
- 2018
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46. Human genetics and molecular mechanisms of vein of Galen malformation.
- Author
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Duran D, Karschnia P, Gaillard JR, Karimy JK, Youngblood MW, DiLuna ML, Matouk CC, Aagaard-Kienitz B, Smith ER, Orbach DB, Rodesch G, Berenstein A, Gunel M, and Kahle KT
- Subjects
- Activin Receptors, Type II genetics, Endoglin genetics, Forecasting, Genes, ras genetics, Humans, Magnetic Resonance Angiography, Mutation genetics, Vein of Galen Malformations pathology, Vein of Galen Malformations therapy, Vein of Galen Malformations genetics
- Abstract
Vein of Galen malformations (VOGMs) are rare developmental cerebrovascular lesions characterized by fistulas between the choroidal circulation and the median prosencephalic vein. Although the treatment of VOGMs has greatly benefited from advances in endovascular therapy, including technical innovation in interventional neuroradiology, many patients are recalcitrant to procedural intervention or lack accessibility to specialized care centers, highlighting the need for improved screening, diagnostics, and therapeutics. A fundamental obstacle to identifying novel targets is the limited understanding of VOGM molecular pathophysiology, including its human genetics, and the lack of an adequate VOGM animal model. Herein, the known human mutations associated with VOGMs are reviewed to provide a framework for future gene discovery. Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation-arteriovenous malformation syndrome ( RASA1) and hereditary hemorrhagic telangiectasia ( ENG and ACVRL1). However, these mutations probably represent only a small fraction of all VOGM cases. Traditional genetic approaches have been limited in their ability to identify additional causative genes for VOGM because kindreds are rare, limited in patient number, and/or seem to have sporadic inheritance patterns, attributable in part to incomplete penetrance and phenotypic variability. The authors hypothesize that the apparent sporadic occurrence of VOGM may frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants. Collaboration among treating physicians, patients' families, and investigators using next-generation sequencing could lead to the discovery of novel genes for VOGM. This could improve the understanding of normal vascular biology, elucidate the pathogenesis of VOGM and possibly other more common arteriovenous malformation subtypes, and pave the way for advances in the diagnosis and treatment of patients with VOGM.
- Published
- 2018
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47. Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia.
- Author
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Kaymakcalan H, Yarman Y, Goc N, Toy F, Meral C, Ercan-Sencicek AG, and Gunel M
- Subjects
- Adolescent, Child, Child, Preschool, Consanguinity, Developmental Disabilities physiopathology, Epilepsy genetics, Epilepsy physiopathology, Exome genetics, Female, Heterozygote, Humans, Intellectual Disability physiopathology, Male, Microcephaly physiopathology, Middle Aged, Mutation, Paraplegia genetics, Paraplegia physiopathology, Pedigree, Phenotype, Siblings, Exome Sequencing, Developmental Disabilities genetics, Intellectual Disability genetics, Microcephaly genetics, Transaminases genetics
- Abstract
We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2018
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48. AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma.
- Author
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Chow RD, Guzman CD, Wang G, Schmidt F, Youngblood MW, Ye L, Errami Y, Dong MB, Martinez MA, Zhang S, Renauer P, Bilguvar K, Gunel M, Sharp PA, Zhang F, Platt RJ, and Chen S
- Subjects
- Animals, Brain Neoplasms drug therapy, Cells, Cultured, Dacarbazine analogs & derivatives, Dacarbazine therapeutic use, Dependovirus genetics, Female, Gene Knock-In Techniques, Gene Knockout Techniques, Glioblastoma drug therapy, Humans, Male, Mice, Mutation, Temozolomide, Brain Neoplasms genetics, CRISPR-Cas Systems, DNA Mutational Analysis, Glioblastoma genetics, Suppression, Genetic genetics, Transcriptome genetics
- Abstract
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m-Nf1, Mll3-Nf1 and Zc3h13-Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo.
- Published
- 2017
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49. Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme.
- Author
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Goods BA, Hernandez AL, Lowther DE, Lucca LE, Lerner BA, Gunel M, Raddassi K, Coric V, Hafler DA, and Love JC
- Subjects
- Antibodies, Blocking therapeutic use, CD4-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation drug effects, Cell Proliferation genetics, Flow Cytometry, Glioblastoma immunology, Healthy Volunteers, Hepatitis A Virus Cellular Receptor 2 metabolism, Humans, Interferon-gamma metabolism, Interleukin-2 therapeutic use, Telomere metabolism, CD4-Positive T-Lymphocytes metabolism, Glioblastoma metabolism, Programmed Cell Death 1 Receptor metabolism
- Abstract
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.
- Published
- 2017
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50. ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features.
- Author
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Çağlayan AO, Sezer RG, Kaymakçalan H, Ulgen E, Yavuz T, Baranoski JF, Bozaykut A, Harmanci AS, Yalcin Y, Youngblood MW, Yasuno K, Bilgüvar K, and Gunel M
- Subjects
- Cardiomyopathies genetics, Child, Preschool, Echocardiography, Exome, Frameshift Mutation, Genetic Predisposition to Disease, Genetic Testing, Heart physiopathology, Homozygote, Humans, Male, Muscle Proteins metabolism, Mutation, Pedigree, Protein Kinases metabolism, Cardiomyopathy, Hypertrophic genetics, Muscle Proteins genetics, Protein Kinases genetics
- Abstract
Primary cardiomyopathy is one of the most common inherited cardiac diseases and harbors significant phenotypic and genetic heterogeneity. Because of this, genetic testing has become standard in treatment of this disease group. Indeed, in recent years, next-generation DNA sequencing has found broad applications in medicine, both as a routine diagnostic tool for genetic disorders and as a high-throughput discovery tool for identifying novel disease-causing genes. We describe a male infant with primary dilated cardiomyopathy who was diagnosed using intrauterine echocardiography and found to progress to hypertrophic cardiomyopathy after birth. This proband was born to a nonconsanguineous family with a past history of a male fetus that died because of cardiac abnormalities at 30 wk of gestation. Using whole-exome sequencing, a novel homozygous frameshift mutation (c.2018delC; p.Gln675SerfsX30) in ALPK3 was identified and confirmed with Sanger sequencing. Heterozygous family members were normal with echocardiographic examination. To date, only two studies have reported homozygous pathogenic variants of ALPK3, with a total of seven affected individuals with cardiomyopathy from four unrelated consanguineous families. We include a discussion of the patient's phenotypic features and a review of relevant literature findings., (© 2017 Çağlayan et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2017
- Full Text
- View/download PDF
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