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25 results on '"Marsh, A. P. L."'

1. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Author

Chung, Changuk, Yang, Xiaoxu, Bae, Taejeong, Vong, Keng Ioi, Mittal, Swapnil, Donkels, Catharina, Westley Phillips, H., Li, Zhen, Marsh, Ashley P. L., Breuss, Martin W., Ball, Laurel L., Garcia, Camila Araújo Bernardino, George, Renee D., Gu, Jing, Xu, Mingchu, Barrows, Chelsea, James, Kiely N., Stanley, Valentina, Nidhiry, Anna S., Khoury, Sami, Howe, Gabrielle, Riley, Emily, Xu, Xin, Copeland, Brett, Wang, Yifan, Kim, Se Hoon, Kang, Hoon-Chul, Schulze-Bonhage, Andreas, Haas, Carola A., Urbach, Horst, Prinz, Marco, Limbrick, Jr., David D., Gurnett, Christina A., Smyth, Matthew D., Sattar, Shifteh, Nespeca, Mark, Gonda, David D., Imai, Katsumi, Takahashi, Yukitoshi, Chen, Hsin-Hung, Tsai, Jin-Wu, Conti, Valerio, Guerrini, Renzo, Devinsky, Orrin, Silva, Jr., Wilson A., Machado, Helio R., Mathern, Gary W., Abyzov, Alexej, Baldassari, Sara, Baulac, Stéphanie, and Gleeson, Joseph G.

Published
2023
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2. Optic Nerve Tilt, Crescent, Ovality, and Torsion in a Multi-Ethnic Cohort of Young Adults With and Without MyopiaONH Characteristics With and Without Myopia

Author

Marsh-Tootle, Wendy L, Harb, Elise, Hou, Wei, Zhang, Qinghua, Anderson, Heather A, Weise, Katherine, Norton, Thomas T, Gwiazda, Jane, and Hyman, Leslie

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Eye Disease and Disorders of Vision, Adult, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Myopia, Optic Disk, Optic Nerve Diseases, Tomography, Optical Coherence, Young Adult, myopia, optical coherence tomography, optic nerve head, Correction of Myopia Evaluation Trial (COMET) Study Group, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract

PurposeThe purpose of this article is to evaluate optic nerve head (ONH) characteristics in an ethnically diverse cohort of young U.S. adults.MethodsIn this study, 409 myopes and 206 nonmyopes (median age 22 years) completed measures including biometry and spectral domain optical coherence tomography from enface (ovality and torsion) and cross-sectional (tilt and crescent width) scans. Associated factors were evaluated using multivariable models.ResultsIn myopic versus nonmyopic right eyes, median tilt (6.0° vs. 2.4°; P < 0.0001) and frequency of crescents (49% vs. 10%; P < 0.0001) were higher in myopes. Right eyes with crescents had higher median tilts (8.8° [myopic], 9.0° [nonmyopic]) than those without crescent (2.5° [myopic], 2.1° [nonmyopic]), irrespective of refractive group (both P < 0.0001). Torsion was similar between groups, with a slight difference in ovality (0.89 vs. 0.91; P < 0.03). Data in the left eyes were similar, and modeling was done only for the right myopic eyes. Multivariable models showed that an increased tilt was associated with ethnicity (P < 0.001), the presence of crescent (P < 0.001), and smaller ONH diameter (P < 0.0031), with interactions between ethnicity and crescent (P = 0.002). Specifically, ONH tilt was significantly higher in Asian eyes without crescent (P < 0.0001 for all comparisons), and crescent width was associated with increased tilt in non-Asian eyes (P < 0.02). Crescent width was associated with ethnicity (greatest in Asians) and disc tilt. Interactions were observed between tilt and ethnicity, whereby tilt had a greater effect on crescent width in non-Asian eyes, and crescent width was associated with increased tilt in non-Asian eyes.ConclusionsThe data clarify the influence of ethnicity and myopia on ONH characteristics in young adults and may inform future studies of biomechanical properties or of retinal pathology of the myopic eye.

Published
2017

3. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

Author

Marsh, Ashley P. L., Edwards, Timothy J., Galea, Charles, Cooper, Helen M., Engle, Elizabeth C., Jamuar, Saumya S., Méneret, Aurélie, Moutard, Marie‐Laure, Nava, Caroline, Rastetter, Agnès, Robinson, Gail, Rouleau, Guy, Roze, Emmanuel, Spencer‐Smith, Megan, Trouillard, Oriane, Billette de Villemeur, Thierry, Walsh, Christopher A., Yu, Timothy W., Heron, Delphine, Sherr, Elliott H., Richards, Linda J., Depienne, Christel, Leventer, Richard J., and Lockhart, Paul J.

Published
2018
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4. Cover Image, Volume 39, Issue 1

Author

Marsh, Ashley P. L., Edwards, Timothy J., Galea, Charles, Cooper, Helen M., Engle, Elizabeth C., Jamuar, Saumya S., Méneret, Aurélie, Moutard, Marie‐Laure, Nava, Caroline, Rastetter, Agnès, Robinson, Gail, Rouleau, Guy, Roze, Emmanuel, Spencer‐Smith, Megan, Trouillard, Oriane, Billette de Villemeur, Thierry, Walsh, Christopher A., Yu, Timothy W., Heron, Delphine, Sherr, Elliott H., Richards, Linda J., Depienne, Christel, Leventer, Richard J., and Lockhart, Paul J.

Published
2018
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6. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

Author

Richard, E. M., Bakhtiari, S., Marsh, A. P. L., Kaiyrzhanov, R., Wagner, M., Shetty, S., Pagnozzi, A., Nordlie, S. M., Guida, B. S., Cornejo, P., Magee, H., Liu, J., Norton, B. Y., Webster, R. I., Worgan, L., Hakonarson, H., Li, J., Guo, Y., Jain, M., Blesson, A., Rodan, L. H., Abbott, M. -A., Comi, A., Cohen, J. S., Alhaddad, B., Meitinger, T., Lenz, D., Ziegler, A., Kotzaeridou, U., Brunet, T., Chassevent, A., Smith-Hicks, C., Ekstein, J., Weiden, T., Hahn, A., Zharkinbekova, N., Turnpenny, P., Tucci, A., Yelton, M., Horvath, R., Gungor, S., Hiz, S., Oktay, Y., Lochmuller, H., Zollino, M., Morleo, M., Marangi, G., Nigro, V., Torella, A., Pinelli, M., Amenta, S., Husain, R. A., Grossmann, B., Rapp, M., Steen, C., Marquardt, I., Grimmel, M., Grasshoff, U., Korenke, G. C., Owczarek-Lipska, M., Neidhardt, J., Radio, F. C., Mancini, C., Claps Sepulveda, D. J., McWalter, K., Begtrup, A., Crunk, A., Guillen Sacoto, M. J., Person, R., Schnur, R. E., Mancardi, M. M., Kreuder, F., Striano, P., Zara, F., Chung, W. K., Marks, W. A., van Eyk, C. L., Webber, D. L., Corbett, M. A., Harper, K., Berry, J. G., MacLennan, A. H., Gecz, J., Tartaglia, M., Salpietro, V., Christodoulou, J., Kaslin, J., Padilla-Lopez, S., Bilguvar, K., Munchau, A., Ahmed, Z. M., Hufnagel, R. B., Fahey, M. C., Maroofian, R., Houlden, H., Sticht, H., Mane, S. M., Rad, A., Vona, B., Jin, S. C., Haack, T. B., Makowski, C., Hirsch, Y., Riazuddin, S., Kruer, M. C., Zollino M. (ORCID:0000-0003-4871-9519), Marangi G. (ORCID:0000-0002-6898-8882), Richard, E. M., Bakhtiari, S., Marsh, A. P. L., Kaiyrzhanov, R., Wagner, M., Shetty, S., Pagnozzi, A., Nordlie, S. M., Guida, B. S., Cornejo, P., Magee, H., Liu, J., Norton, B. Y., Webster, R. I., Worgan, L., Hakonarson, H., Li, J., Guo, Y., Jain, M., Blesson, A., Rodan, L. H., Abbott, M. -A., Comi, A., Cohen, J. S., Alhaddad, B., Meitinger, T., Lenz, D., Ziegler, A., Kotzaeridou, U., Brunet, T., Chassevent, A., Smith-Hicks, C., Ekstein, J., Weiden, T., Hahn, A., Zharkinbekova, N., Turnpenny, P., Tucci, A., Yelton, M., Horvath, R., Gungor, S., Hiz, S., Oktay, Y., Lochmuller, H., Zollino, M., Morleo, M., Marangi, G., Nigro, V., Torella, A., Pinelli, M., Amenta, S., Husain, R. A., Grossmann, B., Rapp, M., Steen, C., Marquardt, I., Grimmel, M., Grasshoff, U., Korenke, G. C., Owczarek-Lipska, M., Neidhardt, J., Radio, F. C., Mancini, C., Claps Sepulveda, D. J., McWalter, K., Begtrup, A., Crunk, A., Guillen Sacoto, M. J., Person, R., Schnur, R. E., Mancardi, M. M., Kreuder, F., Striano, P., Zara, F., Chung, W. K., Marks, W. A., van Eyk, C. L., Webber, D. L., Corbett, M. A., Harper, K., Berry, J. G., MacLennan, A. H., Gecz, J., Tartaglia, M., Salpietro, V., Christodoulou, J., Kaslin, J., Padilla-Lopez, S., Bilguvar, K., Munchau, A., Ahmed, Z. M., Hufnagel, R. B., Fahey, M. C., Maroofian, R., Houlden, H., Sticht, H., Mane, S. M., Rad, A., Vona, B., Jin, S. C., Haack, T. B., Makowski, C., Hirsch, Y., Riazuddin, S., Kruer, M. C., Zollino M. (ORCID:0000-0003-4871-9519), and Marangi G. (ORCID:0000-0002-6898-8882)

Abstract

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Published
2021

8. The energetic brain – A review from students to students

Author

Bordone, Melina Paula, primary, Salman, Mootaz M., additional, Titus, Haley E., additional, Amini, Elham, additional, Andersen, Jens V., additional, Chakraborti, Barnali, additional, Diuba, Artem V., additional, Dubouskaya, Tatsiana G., additional, Ehrke, Eric, additional, Espindola de Freitas, Andiara, additional, Braga de Freitas, Guilherme, additional, Gonçalves, Rafaella A., additional, Gupta, Deepali, additional, Gupta, Richa, additional, Ha, Sharon R., additional, Hemming, Isabel A., additional, Jaggar, Minal, additional, Jakobsen, Emil, additional, Kumari, Punita, additional, Lakkappa, Navya, additional, Marsh, Ashley P. L., additional, Mitlöhner, Jessica, additional, Ogawa, Yuki, additional, Paidi, Ramesh Kumar, additional, Ribeiro, Felipe C., additional, Salamian, Ahmad, additional, Saleem, Suraiya, additional, Sharma, Sorabh, additional, Silva, Joana M., additional, Singh, Shripriya, additional, Sulakhiya, Kunjbihari, additional, Tefera, Tesfaye Wolde, additional, Vafadari, Behnam, additional, Yadav, Anuradha, additional, Yamazaki, Reiji, additional, and Seidenbecher, Constanze I., additional

Published
2019
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9. DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation.

Author

Morcom, Laura, Gobius, Ilan, Marsh, Ashley P. L., Suárez, Rodrigo, Lim, Jonathan W. C., Bridges, Caitlin, Yunan Ye, Fenlon, Laura R., Zagar, Yvrick, Douglass, Amelia M., Donahoo, Amber-Lee S., Fothergill, Thomas, Shaikh, Samreen, Kozulin, Peter, Edwards, Timothy J., Cooper, Helen M., Consortium, IRC5, Sherr, Elliott H., Chédotal, Alain, and Leventer, Richard J.

Published
2021
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10. DCC is required for the development of nociceptive topognosis in mice and humans.

Author

da Silva, Ronan V, Johannssen, Helge C, Wyss, Matthias T, Roome, R Brian, Bourojeni, Farin B, Stifani, Nicolas, Marsh, Ashley P L, Ryan, Monique M, Lockhart, Paul J, Leventer, Richard J, Richards, Linda J, Rosenblatt, Bernard, Srour, Myriam, Weber, Bruno, Zeilhofer, Hanns Ulrich; https://orcid.org/0000-0001-6954-4629, Kania, Artur, da Silva, Ronan V, Johannssen, Helge C, Wyss, Matthias T, Roome, R Brian, Bourojeni, Farin B, Stifani, Nicolas, Marsh, Ashley P L, Ryan, Monique M, Lockhart, Paul J, Leventer, Richard J, Richards, Linda J, Rosenblatt, Bernard, Srour, Myriam, Weber, Bruno, Zeilhofer, Hanns Ulrich; https://orcid.org/0000-0001-6954-4629, and Kania, Artur

Abstract

Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis.

Published
2018

12. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Marsh, Ashley P L, primary, Heron, Delphine, additional, Edwards, Timothy J, additional, Quartier, Angélique, additional, Galea, Charles, additional, Nava, Caroline, additional, Rastetter, Agnès, additional, Moutard, Marie-Laure, additional, Anderson, Vicki, additional, Bitoun, Pierre, additional, Bunt, Jens, additional, Faudet, Anne, additional, Garel, Catherine, additional, Gillies, Greta, additional, Gobius, Ilan, additional, Guegan, Justine, additional, Heide, Solveig, additional, Keren, Boris, additional, Lesne, Fabien, additional, Lukic, Vesna, additional, Mandelstam, Simone A, additional, McGillivray, George, additional, McIlroy, Alissandra, additional, Méneret, Aurélie, additional, Mignot, Cyril, additional, Morcom, Laura R, additional, Odent, Sylvie, additional, Paolino, Annalisa, additional, Pope, Kate, additional, Riant, Florence, additional, Robinson, Gail A, additional, Spencer-Smith, Megan, additional, Srour, Myriam, additional, Stephenson, Sarah E M, additional, Tankard, Rick, additional, Trouillard, Oriane, additional, Welniarz, Quentin, additional, Wood, Amanda, additional, Brice, Alexis, additional, Rouleau, Guy, additional, Attié-Bitach, Tania, additional, Delatycki, Martin B, additional, Mandel, Jean-Louis, additional, Amor, David J, additional, Roze, Emmanuel, additional, Piton, Amélie, additional, Bahlo, Melanie, additional, Billette de Villemeur, Thierry, additional, Sherr, Elliott H, additional, Leventer, Richard J, additional, Richards, Linda J, additional, Lockhart, Paul J, additional, and Depienne, Christel, additional

Published
2017
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13. DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans.

Author

da Silva, Ronan V., Johannssen, Helge C., Wyss, Matthias T., Roome, R. Brian, Bourojeni, Farin B., Stifani, Nicolas, Marsh, Ashley P. L., Ryan, Monique M., Lockhart, Paul J., Leventer, Richard J., Richards, Linda J., Rosenblatt, Bernard, Srour, Myriam, Weber, Bruno, Zeilhofer, Hanns Ulrich, and Kania, Artur

Abstract

Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized pointto- point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis. [ABSTRACT FROM AUTHOR]

Published
2018
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14. Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR

Author

Leventer, R. J., primary, Scerri, T., additional, Marsh, A. P. L., additional, Pope, K., additional, Gillies, G., additional, Maixner, W., additional, MacGregor, D., additional, Harvey, A. S., additional, Delatycki, M. B., additional, Amor, D. J., additional, Crino, P., additional, Bahlo, M., additional, and Lockhart, P. J., additional

Published
2015
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16. Surveillance of Infections Associated With Intravenous Catheters in Dogs and Cats in an Intensive Care Unit.

Author

Marsh-Ng, Michelle L., Burney, Derek P., and Garcia, Jennifer

Subjects
CATHETERS, BACTERIAL cultures, INTRAVENOUS catheterization, ENTEROBACTER, DOGS, CATS
Abstract

Positive catheter-tip culture rates and risk factors associated with bacterial colonization of intravenous (IV) catheters were assessed in dogs and cats. Aerobic and anaerobic bacterial cultures were performed on 151 catheters, and 24.5% were positive. Of the positive cultures, 46.0% grew Enterobacter spp. The type of catheter used, blood sampling through the catheter, the type of IV infusate administered, the duration the catheter was in place, the catheter location, complications with the catheter, and the final outcome of the animal were not associated with an increased risk of a positive bacterial culture from the catheter tip. [ABSTRACT FROM AUTHOR]

Published
2007
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23. DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans

Author

da Silva, Ronan V., Johannssen, Helge C., Wyss, Matthias T., Roome, R. Brian, Bourojeni, Farin B., Stifani, Nicolas, Marsh, Ashley P. L., Ryan, Monique M., Lockhart, Paul J., Leventer, Richard J., Richards, Linda J., Rosenblatt, Bernard, Srour, Myriam, Weber, Bruno, Zeilhofer, Hanns U., and Kania, Artur

Subjects
topographic organization, mirror movement disorder, behavior, commissural, human genetics, spinothalamic, pain, somatosensory system, nociception, mutation, 3. Good health, DCC
Abstract

Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis., Cell Reports, 22 (5), ISSN:2666-3864, ISSN:2211-1247

25. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

Author

Serdal Güngör, Benita Grossmann, Bethany Y. Norton, Zubair M. Ahmed, Wendy K. Chung, John Neidhardt, Julie S. Cohen, Elodie Richard, Yoel Hirsch, Jiankang Li, Jozef Gecz, Ralf A. Husain, Saima Riazuddin, Maria J. Guillen Sacoto, Claudia Steen, Andreas Ziegler, G. Christoph Korenke, Dominic Lenz, Mahim Jain, Urania Kotzaeridou, Henry Houlden, Theresa Brunet, Yavuz Oktay, Semra Hiz, Patricia Cornejo, Sheetal Shetty, Alastair H. MacLennan, Nazira Zharkinbekova, Bader Alhaddad, Dani L. Webber, Mary Alice Abbott, Hanns Lochmüller, Rauan Kaiyrzhanov, Melissa Yelton, Cecilia Mancini, Hakon Hakonarson, Amy Crunk, Simona Amenta, Yiran Guo, Jan Kaslin, Clare L. van Eyk, Richard Webster, Arianna Tucci, Alex M. Pagnozzi, Robert B. Hufnagel, Kirsty McWalter, Sandra M. Nordlie, Kaya Bilguvar, Pasquale Striano, Matias Wagner, Florian Kreuder, Lisa Worgan, Ashley P.L. Marsh, Anna Chassevent, Warren A. Marks, James Liu, Brandon S. Guida, Maria Margherita Mancardi, Kelly Harper, Lance H. Rodan, Rhonda E. Schnur, Dianela Judith Claps Sepulveda, Tzvi Weiden, Michele Pinelli, Marion Rapp, Helen Magee, Jesia G. Berry, Aboulfazl Rad, Michael C. Kruer, Mark A. Corbett, Rita Horvath, Constance Smith-Hicks, Joseph Ekstein, Marta Owczarek-Lipska, Somayeh Bakhtiari, Heinrich Sticht, Thomas Meitinger, Anne M. Comi, Alyssa Blesson, Iris Marquardt, Francesca Clementina Radio, Sergio Padilla-Lopez, Giuseppe Marangi, Christine Makowski, Mona Grimmel, Marco Tartaglia, Sheng Chih Jin, Federico Zara, Andreas Hahn, Shrikant Mane, Michael C Fahey, Marcella Zollino, Barbara Vona, Peter D. Turnpenny, Manuela Morleo, Ute Grasshoff, Amber Begtrup, Richard E. Person, Annalaura Torella, Alexander Münchau, Vincenzo Nigro, Reza Maroofian, John Christodoulou, Tobias B. Haack, Vincenzo Salpietro, Richard, E. M., Bakhtiari, S., Marsh, A. P. L., Kaiyrzhanov, R., Wagner, M., Shetty, S., Pagnozzi, A., Nordlie, S. M., Guida, B. S., Cornejo, P., Magee, H., Liu, J., Norton, B. Y., Webster, R. I., Worgan, L., Hakonarson, H., Li, J., Guo, Y., Jain, M., Blesson, A., Rodan, L. H., Abbott, M. -A., Comi, A., Cohen, J. S., Alhaddad, B., Meitinger, T., Lenz, D., Ziegler, A., Kotzaeridou, U., Brunet, T., Chassevent, A., Smith-Hicks, C., Ekstein, J., Weiden, T., Hahn, A., Zharkinbekova, N., Turnpenny, P., Tucci, A., Yelton, M., Horvath, R., Gungor, S., Hiz, S., Oktay, Y., Lochmuller, H., Zollino, M., Morleo, M., Marangi, G., Nigro, V., Torella, A., Pinelli, M., Amenta, S., Husain, R. A., Grossmann, B., Rapp, M., Steen, C., Marquardt, I., Grimmel, M., Grasshoff, U., Korenke, G. C., Owczarek-Lipska, M., Neidhardt, J., Radio, F. C., Mancini, C., Claps Sepulveda, D. J., Mcwalter, K., Begtrup, A., Crunk, A., Guillen Sacoto, M. J., Person, R., Schnur, R. E., Mancardi, M. M., Kreuder, F., Striano, P., Zara, F., Chung, W. K., Marks, W. A., van Eyk, C. L., Webber, D. L., Corbett, M. A., Harper, K., Berry, J. G., Maclennan, A. H., Gecz, J., Tartaglia, M., Salpietro, V., Christodoulou, J., Kaslin, J., Padilla-Lopez, S., Bilguvar, K., Munchau, A., Ahmed, Z. M., Hufnagel, R. B., Fahey, M. C., Maroofian, R., Houlden, H., Sticht, H., Mane, S. M., Rad, A., Vona, B., Jin, S. C., Haack, T. B., Makowski, C., Hirsch, Y., Riazuddin, S., and Kruer, M. C.

Subjects
Male, Microcephaly, Pathology, Settore MED/03 - GENETICA MEDICA, sensorineural hearing loss, Epilepsy, Neurodevelopmental disorder, sensorineural hearing lo, Genetics (clinical), Allele, ATPases Associated with Diverse Cellular Activitie, medicine.anatomical_structure, Muscle Spasticity, Child, Preschool, Sensorineural hearing loss, Female, movement disorder, medicine.symptom, AAA+ superfamily, Human, Adult, medicine.medical_specialty, Adolescent, Hearing loss, Aaa+ Superfamily, Atpase, Spata5l1, Cerebral Palsy, Intellectual Disability, Movement Disorder, Neurodevelopmental Disorder, Sensorineural Hearing Loss, Biology, Cerebral palsy, White matter, Young Adult, Report, Genetics, medicine, Animals, Humans, ATPase, Genetic Predisposition to Disease, Hearing Loss, SPATA5L1, Hearing Lo, Alleles, cerebral palsy, Periventricular leukomalacia, Animal, Infant, Newborn, Infant, Genetic Variation, medicine.disease, neurodevelopmental disorder, Rats, ATPases Associated with Diverse Cellular Activities, Rat
Abstract

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata511 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata511 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Published
2021

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