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1. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

Author

Mattison, Kari, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George, Menendez, Beatriz, Hoganson, George, Botto, Lorenzo, Filloux, Francis, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke, van der Zwaag, Bert, Aleck, Kyrieckos, Fazenbaker, Andrew, Balciuniene, Jorune, Dubbs, Holly, Marsh, Eric, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina, Deardorff, Matthew, Raca, Gordana, Quindipan, Catherine, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine, Møller, Rikke, Whitney, Andrea, Douglas, Andrew, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie, Tao, James, Sherr, Elliot, Dobyns, William, Baines, Richard, Warwicker, Jim, Parker, J, Banka, Siddharth, Campeau, Philippe, Escayg, Andrew, and Argilli, Emanuela

Subjects
ATP6V0C, V-ATPase, VMA3, epilepsy genetics, neurodevelopmental disorders, Humans, Vacuolar Proton-Translocating ATPases, Saccharomyces cerevisiae, Epilepsy, Adenosine Triphosphate
Abstract

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Published
2023

2. De Novo Variants in RAB11B Cause Various Degrees of Global Developmental Delay and Intellectual Disability in Children

Author

Ahmad, Natalie, Fazeli, Walid, Schließke, Sophia, Lesca, Gaetan, Gokce-Samar, Zeynep, Mekbib, Kedous Y., Jin, Sheng Chih, Burton, Jennifer, Hoganson, George, Petersen, Andrea, Gracie, Sara, Granger, Leslie, Bartels, Enrika, Oppermann, Henry, Kundishora, Adam, Till, Marianne, Milleret-Pignot, Clara, Dangerfield, Shane, Viskochil, David, Anderson, Katherine J., Palculict, Timothy Blake, Schnur, Rhonda E., Wentzensen, Ingrid M., Tiller, George E., Kahle, Kristopher T., Kunz, Wolfram S., Burkart, Sebastian, Simons, Matias, Sticht, Heinrich, Abou Jamra, Rami, and Neuser, Sonja

Published
2023
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3. Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

Author

Ng, Bobby G, Eklund, Erik A, Shiryaev, Sergey A, Dong, Yin Y, Abbott, Mary‐Alice, Asteggiano, Carla, Bamshad, Michael J, Barr, Eileen, Bernstein, Jonathan A, Chelakkadan, Shabeed, Christodoulou, John, Chung, Wendy K, Ciliberto, Michael A, Cousin, Janice, Gardiner, Fiona, Ghosh, Suman, Graf, William D, Grunewald, Stephanie, Hammond, Katherine, Hauser, Natalie S, Hoganson, George E, Houck, Kimberly M, Kohler, Jennefer N, Morava, Eva, Larson, Austin A, Liu, Pengfei, Madathil, Sujana, McCormack, Colleen, Meeks, Naomi JL, Miller, Rebecca, Monaghan, Kristin G, Nickerson, Deborah A, Palculict, Timothy Blake, Papazoglu, Gabriela Magali, Pletcher, Beth A, Scheffer, Ingrid E, Schenone, Andrea Beatriz, Schnur, Rhonda E, Si, Yue, Rowe, Leah J, Russi, Alvaro H Serrano, Russo, Rossana Sanchez, Thabet, Farouq, Tuite, Allysa, Villanueva, María Mercedes, Wang, Raymond Y, Webster, Richard I, Wilson, Dorcas, Zalan, Alice, Network, University of Washington Center for Mendelian Genomics Undiagnosed Diseases, Wolfe, Lynne A, Rosenfeld, Jill A, Rhodes, Lindsay, and Freeze, Hudson H

Subjects
Pediatric, Brain Disorders, Neurosciences, Neurodegenerative, Epilepsy, Biomarkers, Child, Preschool, Congenital Disorders of Glycosylation, Diet, Ketogenic, Female, Glycosylation, Humans, Infant, Male, Mutation, N-Acetylglucosaminyltransferases, Spasms, Infantile, Transferrin, congenital disorders of glycosylation, epilepsy, N-linked glycosylation, whole exome sequencing, Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics, Clinical Sciences, Genetics & Heredity
Abstract

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

Published
2020

4. SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Author

Ng, Bobby G, Sosicka, Paulina, Agadi, Satish, Almannai, Mohammed, Bacino, Carlos A, Barone, Rita, Botto, Lorenzo D, Burton, Jennifer E, Carlston, Colleen, Chung, Brian Hon‐Yin, Cohen, Julie S, Coman, David, Dipple, Katrina M, Dorrani, Naghmeh, Dobyns, William B, Elias, Abdallah F, Epstein, Leon, Gahl, William A, Garozzo, Domenico, Hammer, Trine Bjørg, Haven, Jaclyn, Héron, Delphine, Herzog, Matthew, Hoganson, George E, Hunter, Jesse M, Jain, Mahim, Juusola, Jane, Lakhani, Shenela, Lee, Hane, Lee, Joy, Lewis, Katherine, Longo, Nicola, Lourenço, Charles Marques, Mak, Christopher CY, McKnight, Dianalee, Mendelsohn, Bryce A, Mignot, Cyril, Mirzaa, Ghayda, Mitchell, Wendy, Muhle, Hiltrud, Nelson, Stanley F, Olczak, Mariusz, Palmer, Christina GS, Partikian, Arthur, Patterson, Marc C, Pierson, Tyler M, Quinonez, Shane C, Regan, Brigid M, Ross, M Elizabeth, Sacoto, Maria J Guillen, Scaglia, Fernando, Scheffer, Ingrid E, Segal, Devorah, Singhal, Nilika Shah, Striano, Pasquale, Sturiale, Luisa, Symonds, Joseph D, Tang, Sha, Vilain, Eric, Willis, Mary, Wolfe, Lynne A, Yang, Hui, Yano, Shoji, Powis, Zöe, Suchy, Sharon F, Rosenfeld, Jill A, Edmondson, Andrew C, Grunewald, Stephanie, and Freeze, Hudson H

Subjects
Clinical Research, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, Animals, Biopsy, CHO Cells, Cells, Cultured, Congenital Disorders of Glycosylation, Cricetulus, Female, Humans, Male, Monosaccharide Transport Proteins, Mutation, Uridine Diphosphate Galactose, congenital disorders of glycosylation, glycoside, nucleotide sugar transporter, UDP-galactose, Clinical Sciences, Genetics & Heredity
Abstract

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Published
2019

5. Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy

Author

Peng, Yanyan, Shinde, Deepali N, Valencia, C Alexander, Mo, Jun-Song, Rosenfeld, Jill, Cho, Megan Truitt, Chamberlin, Adam, Li, Zhuo, Liu, Jie, Gui, Baoheng, Brockhage, Rachel, Basinger, Alice, Alvarez-Leon, Brenda, Heydemann, Peter, Magoulas, Pilar L, Lewis, Andrea M, Scaglia, Fernando, Gril, Solange, Chong, Shuk Ching, Bower, Matthew, Monaghan, Kristin G, Willaert, Rebecca, Plona, Maria-Renee, Dineen, Rich, Milan, Francisca, Hoganson, George, Powis, Zoe, Helbig, Katherine L, Keller-Ramey, Jennifer, Harris, Belinda, Anderson, Laura C, Green, Torrian, Rizzo, Stacey J Sukoff, Kaylor, Julie, Chen, Jiani, Guan, Min-Xin, Sellars, Elizabeth, Sparagana, Steven P, Gibson, James B, Reinholdt, Laura G, Tang, Sha, and Huang, Taosheng

Subjects
Neurosciences, Eye Disease and Disorders of Vision, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adolescent, Alleles, Animals, Child, Child, Preschool, Electron Transport, Female, Ferredoxins, Humans, Infant, Iron, Iron-Sulfur Proteins, Male, Mice, Mitochondria, Mitochondrial Membranes, Mutagenesis, Mutation, Optic Atrophy, Oxidoreductases, Pedigree, Sulfite Reductase (Ferredoxin), Exome Sequencing, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.

Published
2017

6. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Küry, Sébastien, van Woerden, Geeske M, Besnard, Thomas, Onori, Martina Proietti, Latypova, Xénia, Towne, Meghan C, Cho, Megan T, Prescott, Trine E, Ploeg, Melissa A, Sanders, Stephan, Stessman, Holly AF, Pujol, Aurora, Distel, Ben, Robak, Laurie A, Bernstein, Jonathan A, Denommé-Pichon, Anne-Sophie, Lesca, Gaëtan, Sellars, Elizabeth A, Berg, Jonathan, Carré, Wilfrid, Busk, Øyvind Løvold, van Bon, Bregje WM, Waugh, Jeff L, Deardorff, Matthew, Hoganson, George E, Bosanko, Katherine B, Johnson, Diana S, Dabir, Tabib, Holla, Øystein Lunde, Sarkar, Ajoy, Tveten, Kristian, de Bellescize, Julitta, Braathen, Geir J, Terhal, Paulien A, Grange, Dorothy K, van Haeringen, Arie, Lam, Christina, Mirzaa, Ghayda, Burton, Jennifer, Bhoj, Elizabeth J, Douglas, Jessica, Santani, Avni B, Nesbitt, Addie I, Helbig, Katherine L, Andrews, Marisa V, Begtrup, Amber, Tang, Sha, van Gassen, Koen LI, Juusola, Jane, Foss, Kimberly, Enns, Gregory M, Moog, Ute, Hinderhofer, Katrin, Paramasivam, Nagarajan, Lincoln, Sharyn, Kusako, Brandon H, Lindenbaum, Pierre, Charpentier, Eric, Nowak, Catherine B, Cherot, Elouan, Simonet, Thomas, Ruivenkamp, Claudia AL, Hahn, Sihoun, Brownstein, Catherine A, Xia, Fan, Schmitt, Sébastien, Deb, Wallid, Bonneau, Dominique, Nizon, Mathilde, Quinquis, Delphine, Chelly, Jamel, Rudolf, Gabrielle, Sanlaville, Damien, Parent, Philippe, Gilbert-Dussardier, Brigitte, Toutain, Annick, Sutton, Vernon R, Thies, Jenny, Peart-Vissers, Lisenka ELM, Boisseau, Pierre, Vincent, Marie, Grabrucker, Andreas M, Dubourg, Christèle, Network, Undiagnosed Diseases, Tan, Wen-Hann, Verbeek, Nienke E, Granzow, Martin, Santen, Gijs WE, Shendure, Jay, Isidor, Bertrand, Pasquier, Laurent, Redon, Richard, Yang, Yaping, State, Matthew W, Kleefstra, Tjitske, Cogné, Benjamin, HUGO, GEM, Study, Deciphering Developmental Disorders, Petrovski, Slavé, and Retterer, Kyle

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Neurosciences, Brain Disorders, Genetics, Intellectual and Developmental Disabilities (IDD), Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Brain, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Line, Exome, Female, Glutamic Acid, HEK293 Cells, Humans, Intellectual Disability, Male, Mice, Mice, Inbred C57BL, Mutation, Neurons, Phosphorylation, Signal Transduction, Undiagnosed Diseases Network, GEM HUGO, Deciphering Developmental Disorders Study, AMPAR, CAMK2, CAMK2A, CAMK2B, NMDAR, de novo mutations, intellectual disability, synaptic plasticity, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017

7. Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

Author

Dworschak, Gabriel C., Punetha, Jaya, Kalanithy, Jeshurun C., Mingardo, Enrico, Erdem, Haktan B., Akdemir, Zeynep C., Karaca, Ender, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Jhangiani, Shalini N., Hunter, Jill V., Dakal, Tikam Chand, Dhabhai, Bhanupriya, Dabbagh, Omar, Alsaif, Hessa S., Alkuraya, Fowzan S., Maroofian, Reza, Houlden, Henry, Efthymiou, Stephanie, Dominik, Natalia, Salpietro, Vincenzo, Sultan, Tipu, Haider, Shahzad, Bibi, Farah, Thiele, Holger, Hoefele, Julia, Riedhammer, Korbinian M., Wagner, Matias, Guella, Ilaria, Demos, Michelle, Keren, Boris, Buratti, Julien, Charles, Perrine, Nava, Caroline, Héron, Delphine, Heide, Solveig, Valkanas, Elise, Waddell, Leigh B., Jones, Kristi J., Oates, Emily C., Cooper, Sandra T., MacArthur, Daniel, Syrbe, Steffen, Ziegler, Andreas, Platzer, Konrad, Okur, Volkan, Chung, Wendy K., O’Shea, Sarah A., Alcalay, Roy, Fahn, Stanley, Mark, Paul R., Guerrini, Renzo, Vetro, Annalisa, Hudson, Beth, Schnur, Rhonda E., Hoganson, George E., Burton, Jennifer E., McEntagart, Meriel, Lindenberg, Tobias, Yilmaz, Öznur, Odermatt, Benjamin, Pehlivan, Davut, Posey, Jennifer E., Lupski, James R., and Reutter, Heiko

Published
2021
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8. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Amor, David J., Baxová, Alice, Bendová, Šárka, Biamino, Elisa, Brusco, Alfredo, Caluseriu, Oana, Cox, Nancy J., Froukh, Tawfiq, Gunay-Aygun, Meral, Hančárová, Miroslava, Haynes, Devon, Heide, Solveig, Hoganson, George, Kaname, Tadashi, Keren, Boris, Kosaki, Kenjiro, Kubota, Kazuo, Lemons, Jennifer M., Magriña, Maria A., Mark, Paul R., McDonald, Marie T., Montgomery, Sarah, Morley, Gina M., Ohnishi, Hidenori, Okamoto, Nobuhiko, Rodriguez-Buritica, David, Rump, Patrick, Sedláček, Zdeněk, Schatz, Krista, Streff, Haley, Uehara, Tomoko, Walia, Jagdeep S., Wheeler, Patricia G., Wiesener, Antje, Zweier, Christiane, Kawakami, Koichi, Wentzensen, Ingrid M., Lalani, Seema R., Siu, Victoria M., Bi, Weimin, and Balci, Tugce B.

Published
2021
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14. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

Author

Genetica Klinische Genetica, Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, Escayg, Andrew, Genetica Klinische Genetica, Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Published
2023

15. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

Author

Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Angel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van der Zwaag, Bert, Aleck, Kyrieckos A, Fazenbaker, Andrew C, Balciuniene, Jorune, Dubbs, Holly A, Marsh, Eric D, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina E, Deardorff, Matthew A, Raca, Gordana, Quindipan, Catherine, Van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjorg, Moller, Rikke S, Whitney, Andrea, Douglas, Andrew GL, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argilli, Emanuela, Sherr, Elliot H, Dobyns, William B, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Subjects
neurodevelopmental disorders, ATP6V0C, VMA3, V-ATPase, Neurology (clinical), epilepsy genetics
Abstract

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms. ispartof: BRAIN vol:146 issue:4 ispartof: location:England status: Published online

Published
2023

16. ATP6V0C variants impair vacuolar V-ATPase causing a neurodevelopmental disorder often associated with epilepsy

Author

Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, Escayg, Andrew, Mattison, Kari A, Tossing, Gille, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, Mccann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Subjects
neurodevelopmental disorders, ATP6V0C, VMA3, epilepsy genetic, V-ATPase
Abstract

The vacuolar H+-ATPase (V-ATPase) is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the V-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modeling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased V-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behavior, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction, and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder, and provides insight into disease mechanisms.

Published
2022

17. Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

Author

AlAbdi, Lama, Desbois, Muriel, Rusnac, Domniţa-Valeria, Sulaiman, Raashda A, Rosenfeld, Jill A, Lalani, Seema, Murdock, David R, Burrage, Lindsay C, Network, Undiagnosed Diseases, Au, Ping Yee Billie, Towner, Shelley, Wilson, William G, Wong, Lawrence, Brunet, Theresa, Strobl-Wildemann, Gertrud, Burton, Jennifer E, Hoganson, George, McWalter, Kirsty, Begtrup, Amber, and Zarate, Yuri A

Subjects
CORPUS callosum, DYSGENESIS, GENOME editing, PHENOTYPES, AGENESIS of corpus callosum, CEREBRAL hemispheres, DEVELOPMENTAL delay, EPILEPSY
Abstract

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2 , a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2 -related developmental delay with corpus callosum defects (MDCD). [ABSTRACT FROM AUTHOR]

Published
2023
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18. Comparison of psychosine analysis in dried blood spots and red blood cells from children with Krabbe disease

Author

White, Amy L., primary, Escolar, Maria L., additional, Peck, Dawn, additional, Pino, Gisele, additional, Studinski, April, additional, Hoganson, George E., additional, Kurtzberg, Joanne, additional, Raymond, Kimiyo, additional, Gavrilov, Dimitar, additional, Oglesbee, Devin, additional, Tortorelli, Silvia, additional, and Matern, Dietrich, additional

Published
2022
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21. Comparison of psychosine analysis in dried blood spots and red blood cells in Krabbe disease

Author

White, Amy, primary, Guenzel, Adam, additional, Turgeon, Coleman, additional, Escolar, Maria, additional, Peck, Dawn, additional, Pino, Gisele, additional, Studinski, April, additional, Hoganson, George, additional, Baker, Peter, additional, Rubin, Jennifer, additional, Strong, Alanna, additional, Hickey, Rachel, additional, Burton, Jennifer, additional, Engelhardt, Nicole, additional, Sremba, Leighann, additional, Chen, Sharon, additional, Bialer, Martin, additional, Pisani, Laura, additional, Prasad, Vinod, additional, Kurtzberg, Joanne, additional, Orsini, Joseph, additional, Gelb, Michael, additional, Raymond, Kimiyo, additional, Oglesbee, Devin, additional, Gavrilov, Dimitar, additional, Tortorelli, Silvia, additional, Rinaldo, Piero, additional, and Matern, Dietrich, additional

Published
2021
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22. Improving the performance of newborn screening for mucopolysaccharidosis type II with second tier biomarker testing

Author

Peck, Dawn, primary, White, Amy, additional, Pino, Gisele, additional, Studinski, April, additional, Strenk, Meghan, additional, Gadea, Randi, additional, Gannon, Jennifer, additional, Heese, Bryce, additional, Font-Montgomery, Esperanza, additional, Klug, Tracy, additional, Burton, Jennifer, additional, Hoganson, George, additional, Oglesbee, Devin, additional, Gavrilov, Dimitar, additional, Matern, Dietrich, additional, Raymond, Kimiyo, additional, Rinaldo, Piero, additional, and Tortorelli, Silvia, additional

Published
2021
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23. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, de Brouwer, Arjan P M, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, and de Brouwer, Arjan P M

Abstract

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.

Published
2020

24. De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Chilton, Ilana, Okur, Volkan, Vitiello, Giuseppina, Selicorni, Angelo, Mariani, Milena, Goldenberg, Alice, Husson, Thomas, Campion, Dominique, Lichtenbelt, Klaske D, van Gassen, Koen, Steinraths, Michelle, Rice, Jennifer, Roeder, Elizabeth R, Littlejohn, Rebecca O, Srour, Myriam, Sebire, Guillaume, Accogli, Andrea, Héron, Delphine, Heide, Solveig, Nava, Caroline, Depienne, Christel, Larson, Austin, Niyazov, Dmitriy, Azage, Meron, Hoganson, George, Burton, Jennifer, Rush, Eric T, Jenkins, Janda L, Saunders, Carol J, Thiffault, Isabelle, Alaimo, Joseph T, Fleischer, Julie, Groepper, Daniel, Gripp, Karen W, Chung, Wendy K, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Chilton, Ilana, Okur, Volkan, Vitiello, Giuseppina, Selicorni, Angelo, Mariani, Milena, Goldenberg, Alice, Husson, Thomas, Campion, Dominique, Lichtenbelt, Klaske D, van Gassen, Koen, Steinraths, Michelle, Rice, Jennifer, Roeder, Elizabeth R, Littlejohn, Rebecca O, Srour, Myriam, Sebire, Guillaume, Accogli, Andrea, Héron, Delphine, Heide, Solveig, Nava, Caroline, Depienne, Christel, Larson, Austin, Niyazov, Dmitriy, Azage, Meron, Hoganson, George, Burton, Jennifer, Rush, Eric T, Jenkins, Janda L, Saunders, Carol J, Thiffault, Isabelle, Alaimo, Joseph T, Fleischer, Julie, Groepper, Daniel, Gripp, Karen W, and Chung, Wendy K

Published
2020

26. Genotype–phenotype correlation at codon 1740 ofSETD2

Author

Rabin, Rachel, primary, Radmanesh, Alireza, additional, Glass, Ian A., additional, Dobyns, William B., additional, Aldinger, Kimberly A., additional, Shieh, Joseph T., additional, Romoser, Shelby, additional, Bombei, Hannah, additional, Dowsett, Leah, additional, Trapane, Pamela, additional, Bernat, John A., additional, Baker, Janice, additional, Mendelsohn, Nancy J., additional, Popp, Bernt, additional, Siekmeyer, Manuela, additional, Sorge, Ina, additional, Sansbury, Francis Hugh, additional, Watts, Patrick, additional, Foulds, Nicola C., additional, Burton, Jennifer, additional, Hoganson, George, additional, Hurst, Jane A., additional, Menzies, Lara, additional, Osio, Deborah, additional, Kerecuk, Larissa, additional, Cobben, Jan M., additional, Jizi, Khadijé, additional, Jacquemont, Sebastien, additional, Bélanger, Stacey A., additional, Löhner, Katharina, additional, Veenstra‐Knol, Hermine E., additional, Lemmink, Henny H., additional, Keller‐Ramey, Jennifer, additional, Wentzensen, Ingrid M., additional, Punj, Sumit, additional, McWalter, Kirsty, additional, Lenberg, Jerica, additional, Ellsworth, Katarzyna A., additional, Radtke, Kelly, additional, Akbarian, Schahram, additional, and Pappas, John, additional

Published
2020
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27. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay

Author

Vissers, Lisenka E.L.M., primary, Kalvakuri, Sreehari, additional, de Boer, Elke, additional, Geuer, Sinje, additional, Oud, Machteld, additional, van Outersterp, Inge, additional, Kwint, Michael, additional, Witmond, Melde, additional, Kersten, Simone, additional, Polla, Daniel L., additional, Weijers, Dilys, additional, Begtrup, Amber, additional, McWalter, Kirsty, additional, Ruiz, Anna, additional, Gabau, Elisabeth, additional, Morton, Jenny E.V., additional, Griffith, Christopher, additional, Weiss, Karin, additional, Gamble, Candace, additional, Bartley, James, additional, Vernon, Hilary J., additional, Brunet, Kendra, additional, Ruivenkamp, Claudia, additional, Kant, Sarina G., additional, Kruszka, Paul, additional, Larson, Austin, additional, Afenjar, Alexandra, additional, Billette de Villemeur, Thierry, additional, Nugent, Kimberly, additional, Raymond, F. Lucy, additional, Venselaar, Hanka, additional, Demurger, Florence, additional, Soler-Alfonso, Claudia, additional, Li, Dong, additional, Bhoj, Elizabeth, additional, Hayes, Ian, additional, Hamilton, Nina Powell, additional, Ahmad, Ayesha, additional, Fisher, Rachel, additional, van den Born, Myrthe, additional, Willems, Marjolaine, additional, Sorlin, Arthur, additional, Delanne, Julian, additional, Moutton, Sebastien, additional, Christophe, Philippe, additional, Mau-Them, Frederic Tran, additional, Vitobello, Antonio, additional, Goel, Himanshu, additional, Massingham, Lauren, additional, Phornphutkul, Chanika, additional, Schwab, Jennifer, additional, Keren, Boris, additional, Charles, Perrine, additional, Vreeburg, Maaike, additional, De Simone, Lenika, additional, Hoganson, George, additional, Iascone, Maria, additional, Milani, Donatella, additional, Evenepoel, Lucie, additional, Revencu, Nicole, additional, Ward, D. Isum, additional, Burns, Kaitlyn, additional, Krantz, Ian, additional, Raible, Sarah E., additional, Murrell, Jill R., additional, Wood, Kathleen, additional, Cho, Megan T., additional, van Bokhoven, Hans, additional, Muenke, Maximilian, additional, Kleefstra, Tjitske, additional, Bodmer, Rolf, additional, and de Brouwer, Arjan P.M., additional

Published
2020
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28. De novo heterozygous missense and loss‐of‐function variants in CDC42BPB are associated with a neurodevelopmental phenotype

Author

Chilton, Ilana, primary, Okur, Volkan, additional, Vitiello, Giuseppina, additional, Selicorni, Angelo, additional, Mariani, Milena, additional, Goldenberg, Alice, additional, Husson, Thomas, additional, Campion, Dominique, additional, Lichtenbelt, Klaske D., additional, Gassen, Koen, additional, Steinraths, Michelle, additional, Rice, Jennifer, additional, Roeder, Elizabeth R., additional, Littlejohn, Rebecca O., additional, Srour, Myriam, additional, Sebire, Guillaume, additional, Accogli, Andrea, additional, Héron, Delphine, additional, Heide, Solveig, additional, Nava, Caroline, additional, Depienne, Christel, additional, Larson, Austin, additional, Niyazov, Dmitriy, additional, Azage, Meron, additional, Hoganson, George, additional, Burton, Jennifer, additional, Rush, Eric T., additional, Jenkins, Janda L., additional, Saunders, Carol J., additional, Thiffault, Isabelle, additional, Alaimo, Joseph T., additional, Fleischer, Julie, additional, Groepper, Daniel, additional, Gripp, Karen W., additional, and Chung, Wendy K., additional

Published
2020
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29. Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants

Author

Burton, Barbara K., primary, Charrow, Joel, additional, Hoganson, George E., additional, Fleischer, Julie, additional, Grange, Dorothy K., additional, Braddock, Stephen R., additional, Hitchins, Lauren, additional, Hickey, Rachel, additional, Christensen, Katherine M., additional, Groepper, Daniel, additional, Shryock, Heather, additional, Smith, Pamela, additional, Shao, Rong, additional, and Basheeruddin, Khaja, additional

Published
2020
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30. Infantile systemic hyalinosis

Author

Shin, Helen T., Paller, Amy, Hoganson, George, Willner, Judith P., Chang, Mary Wu, and Orlow, Seth J.

Published
2004

35. Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome

Author

Vasileiou, Georgia, Vergarajauregui, Silvia, Endele, Sabine, Popp, Bernt, Buettner, Christian, Ekici, Arif B., Gerard, Marion, Bramswig, Nuria C., Albrecht, Beate, Clayton-Smith, Jill, Morton, Jenny, Tomkins, Susan, Low, Karen, Weber, Astrid, Wenzel, Maren, Altmueller, Janine, Li, Yun, Wollnik, Bernd, Hoganson, George, Plona, Maria-Renee, Cho, Megan T., Thiel, Christian T., Luedecke, Hermann-Josef, Strom, Tim M., Calpena, Eduardo, Wilkie, Andrew O. M., Wieczorek, Dagmar, Engel, Felix B., Reis, Andre, Vasileiou, Georgia, Vergarajauregui, Silvia, Endele, Sabine, Popp, Bernt, Buettner, Christian, Ekici, Arif B., Gerard, Marion, Bramswig, Nuria C., Albrecht, Beate, Clayton-Smith, Jill, Morton, Jenny, Tomkins, Susan, Low, Karen, Weber, Astrid, Wenzel, Maren, Altmueller, Janine, Li, Yun, Wollnik, Bernd, Hoganson, George, Plona, Maria-Renee, Cho, Megan T., Thiel, Christian T., Luedecke, Hermann-Josef, Strom, Tim M., Calpena, Eduardo, Wilkie, Andrew O. M., Wieczorek, Dagmar, Engel, Felix B., and Reis, Andre

Abstract

Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

Published
2018

37. Haploinsufficiency of PRR12causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Amor, David J., Baxová, Alice, Bendová, Šárka, Biamino, Elisa, Brusco, Alfredo, Caluseriu, Oana, Cox, Nancy J., Froukh, Tawfiq, Gunay-Aygun, Meral, Hančárová, Miroslava, Haynes, Devon, Heide, Solveig, Hoganson, George, Kaname, Tadashi, Keren, Boris, Kosaki, Kenjiro, Kubota, Kazuo, Lemons, Jennifer M., Magriña, Maria A., Mark, Paul R., McDonald, Marie T., Montgomery, Sarah, Morley, Gina M., Ohnishi, Hidenori, Okamoto, Nobuhiko, Rodriguez-Buritica, David, Rump, Patrick, Sedláček, Zdeněk, Schatz, Krista, Streff, Haley, Uehara, Tomoko, Walia, Jagdeep S., Wheeler, Patricia G., Wiesener, Antje, Zweier, Christiane, Kawakami, Koichi, Wentzensen, Ingrid M., Lalani, Seema R., Siu, Victoria M., Bi, Weimin, and Balci, Tugce B.

Abstract

Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.

Published
2021
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38. Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome

Author

Vasileiou, Georgia, primary, Vergarajauregui, Silvia, additional, Endele, Sabine, additional, Popp, Bernt, additional, Büttner, Christian, additional, Ekici, Arif B., additional, Gerard, Marion, additional, Bramswig, Nuria C., additional, Albrecht, Beate, additional, Clayton-Smith, Jill, additional, Morton, Jenny, additional, Tomkins, Susan, additional, Low, Karen, additional, Weber, Astrid, additional, Wenzel, Maren, additional, Altmüller, Janine, additional, Li, Yun, additional, Wollnik, Bernd, additional, Hoganson, George, additional, Plona, Maria-Renée, additional, Cho, Megan T., additional, Thiel, Christian T., additional, Lüdecke, Hermann-Josef, additional, Strom, Tim M., additional, Calpena, Eduardo, additional, Wilkie, Andrew O.M., additional, Wieczorek, Dagmar, additional, Engel, Felix B., additional, and Reis, André, additional

Published
2018
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39. Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome

Author

Helgeson, Maria, primary, Keller-Ramey, Jennifer, additional, Knight Johnson, Amy, additional, Lee, Jennifer A., additional, Magner, Daniel B., additional, Deml, Brett, additional, Deml, Jacea, additional, Hu, Ying-Ying, additional, Li, Zejuan, additional, Donato, Kirsten, additional, Das, Soma, additional, Laframboise, Rachel, additional, Tremblay, Sandra, additional, Krantz, Ian, additional, Noon, Sarah, additional, Hoganson, George, additional, Burton, Jennifer, additional, Schaaf, Christian P., additional, and del Gaudio, Daniela, additional

Published
2017
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40. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Küry, Sébastien, van Woerden, Geeske M, Besnard, Thomas, Proietti Onori, Martina, Latypova, Xénia, Towne, Meghan C, Cho, Megan T., Prescott, Trine E, Ploeg, Melissa A, Sanders, Jan-Stephan, Stessman, Holly A F, Pujol, Aurora, Distel, Ben, Robak, Laurie A, Bernstein, Jonathan A, Denommé-Pichon, Anne-Sophie, Lesca, Gaëtan, Sellars, Elizabeth A, Berg, Jonathan, Carré, Wilfrid, Busk, Øyvind Løvold, van Bon, Bregje W M, Waugh, Jeff L, Deardorff, Matthew, Hoganson, George E, Bosanko, Katherine B, Johnson, Diana S, Dabir, Tabib, Holla, Øystein Lunde, Sarkar, Ajoy, Tveten, Kristian, de Bellescize, Julitta, Braathen, Geir J, Terhal, Paulien A, Grange, Dorothy K, van Haeringen, Arie, Lam, Christina, Mirzaa, Ghayda, Burton, Jennifer, Bhoj, Elizabeth J., Douglas, Jessica, Santani, Avni B, Nesbitt, Addie I, Helbig, Katherine L, Andrews, Marisa V, Begtrup, Amber, Tang, Sha, van Gassen, Koen L I, Juusola, Jane, Verbeek, Nienke E, Undiagnosed Diseases Network, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Küry, Sébastien, van Woerden, Geeske M, Besnard, Thomas, Proietti Onori, Martina, Latypova, Xénia, Towne, Meghan C, Cho, Megan T., Prescott, Trine E, Ploeg, Melissa A, Sanders, Jan-Stephan, Stessman, Holly A F, Pujol, Aurora, Distel, Ben, Robak, Laurie A, Bernstein, Jonathan A, Denommé-Pichon, Anne-Sophie, Lesca, Gaëtan, Sellars, Elizabeth A, Berg, Jonathan, Carré, Wilfrid, Busk, Øyvind Løvold, van Bon, Bregje W M, Waugh, Jeff L, Deardorff, Matthew, Hoganson, George E, Bosanko, Katherine B, Johnson, Diana S, Dabir, Tabib, Holla, Øystein Lunde, Sarkar, Ajoy, Tveten, Kristian, de Bellescize, Julitta, Braathen, Geir J, Terhal, Paulien A, Grange, Dorothy K, van Haeringen, Arie, Lam, Christina, Mirzaa, Ghayda, Burton, Jennifer, Bhoj, Elizabeth J., Douglas, Jessica, Santani, Avni B, Nesbitt, Addie I, Helbig, Katherine L, Andrews, Marisa V, Begtrup, Amber, Tang, Sha, van Gassen, Koen L I, Juusola, Jane, Verbeek, Nienke E, and Undiagnosed Diseases Network

Published
2017

41. Acute disseminated encephalomyelitis in China, Singapore, and Japan: a comparison with the U.S.A. (P2.380)

Author

Koelman, Diederik, primary, Benkeser, David, additional, Xu, Yan, additional, Neo, Shermyn, additional, Tan, Kevin, additional, Katsuno, Masahisa, additional, Sobue, Gen, additional, Natsume, Jun, additional, Chahin, Salim, additional, Mar, Soe, additional, Venkatesan, Arun, additional, Chitnis, Tanuja, additional, Hoganson, George, additional, Yeshokumar, Anusha, additional, Barreras, Paula, additional, Majmudar, Bittu, additional, Carone, Marco, additional, and Mateen, Farrah, additional

Published
2017
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42. Mudd's disease (MAT I/III deficiency) : a survey of data for MAT1A homozygotes and compound heterozygotes

Author

Chien, Yin-Hsiu, Abdenur, Jose E., Baronio, Federico, Bannick, Allison Anne, Corrales, Fernando, Couce, Maria, Donner, Markus G., Ficicioglu, Can, Freehauf, Cynthia, Frithiof, Deborah, Gotway, Garrett, Hirabayashi, Koichi, Hofstede, FC, Hoganson, George, Hwu, Wuh-Liang, James, Philip, Kim, Sook, Korman, Stanley H., Lachmann, Robin, Levy, Harvey, Lindner, Martin, Lykopoulou, Lilia, Mayatepek, Ertan, Muntau, Ania, Okano, Yoshiyuki, Raymond, Kimiyo, Rubio-Gozalbo, Estela, Scholl-Buergi, Sabine, Schulze, Andreas, Singh, Rani, Stabler, Sally, Stuy, Mary, Thomas, Janet, Wagner, Conrad, Wilson, William G., Wortmann, Saskia, Yamamoto, Shigenori, Pao, Maryland, and Blom, Henk J.

Subjects
EXPRESSION, PERSISTENT HYPERMETHIONINEMIA, BLOOD-BRAIN-BARRIER, Research Support, Non-U.S. Gov't, Review, Research Support, N.I.H., Intramural, S-ADENOSYLMETHIONINE SYNTHETASE, DOMINANT INHERITANCE, CEREBROSPINAL-FLUID, PLASMA TOTAL HOMOCYSTEINE, Journal Article, METHIONINE ADENOSYLTRANSFERASE-I/III, MESSENGER-RNA, MUTATION
Abstract

Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine beta-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. Results and Discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 mu M or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.

Published
2015

43. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative

Author

Bentler, Kristi, primary, Zhai, Shaohui, additional, Elsbecker, Sara A., additional, Arnold, Georgianne L., additional, Burton, Barbara K., additional, Vockley, Jerry, additional, Cameron, Cynthia A., additional, Hiner, Sally J., additional, Edick, Mathew J., additional, Berry, Susan A., additional, Thomas, Janet, additional, Dodge, Melinda, additional, Singh, Rani, additional, Lakshman, Sangeetha, additional, Coakley, Katie, additional, Stembridge, Adrya, additional, Russi, Alvaro Serrano, additional, Phillips, Emily, additional, Burton, Barbara, additional, Edano, Clare, additional, Shrestha, Sheela, additional, Hoganson, George, additional, Dwyer, Lauren, additional, Hainline, Bryan, additional, Romie, Susan, additional, Hainline, Sarah, additional, Asamoah, Alexander, additional, Goodin, Kara, additional, Rajakaruna, Cecilia, additional, Jackson, Kelly, additional, Hamosh, Ada, additional, Vernon, Hilary, additional, Smith, Nancy, additional, Ahmad, Ayesha, additional, Lipinski, Sue, additional, Feldman, Gerald, additional, Berry, Susan, additional, Elsbecker, Sara, additional, Bentler, Kristi, additional, Font-Montgomery, Esperanza, additional, Peck, Dawn, additional, Pena, Loren D.M., additional, Koeberl, Dwight D., additional, Jiang, Yong-hui, additional, Kishnani, Priya S., additional, Rizzo, William, additional, Dawson, Machelle, additional, Ambrose, Nancy, additional, Levy, Paul, additional, Kronn, David, additional, Fong, Chin-to, additional, D’Aco, Kristin, additional, Hart, Theresa, additional, Erbe, Richard, additional, Samons, Melissa, additional, Leslie, Nancy, additional, Powers, Racheal, additional, Bartholomew, Dennis, additional, Goff, Melanie, additional, vanCalcar, Sandy, additional, Hansen, Joyanna, additional, Arnold, Georgianne, additional, Walsh-Vockley, Cate, additional, Rhead, William, additional, Dimmock, David, additional, Engelking, Paula, additional, Bird, Cassie, additional, Swan, Ashley, additional, Schwoerer, Jessica Scott, additional, Henry, Sonja, additional, Narumanchi, TaraChandra, additional, Hummel, Marybeth, additional, Wilkins, Jennie, additional, Davis-Keppen, Laura, additional, Stein, Quinn, additional, Loman, Rebecca, additional, Cameron, Cynthia, additional, and Justice, Kaitlin, additional

Published
2016
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44. Acute disseminated encephalomyelitis in 228 patients

Author

Koelman, Diederik L.H., primary, Chahin, Salim, additional, Mar, Soe S., additional, Venkatesan, Arun, additional, Hoganson, George M., additional, Yeshokumar, Anusha K., additional, Barreras, Paula, additional, Majmudar, Bittu, additional, Klein, Joshua P., additional, Chitnis, Tanuja, additional, Benkeser, David C., additional, Carone, Marco, additional, and Mateen, Farrah J., additional

Published
2016
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45. Newborn screening for lysosomal disorders in Illinois

Author

Burton, Barbara K., primary, Hoganson, George E., additional, Charrow, Joel, additional, Tinkle, Brad, additional, Dimmock, David, additional, Waggoner, Darrel, additional, Grange, Dorothy, additional, Nash, Claudia, additional, Becker, Jean, additional, Shao, Rong, additional, Basheeruddin, Khaja, additional, and Dizikes, George, additional

Published
2016
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46. Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes

Author

MDL patientenzorg, Child Health, Chien, Yin-Hsiu, Abdenur, Jose E., Baronio, Federico, Bannick, Allison Anne, Corrales, Fernando, Couce, Maria, Donner, Markus G., Ficicioglu, Can, Freehauf, Cynthia, Frithiof, Deborah, Gotway, Garrett, Hirabayashi, Koichi, Hofstede, FC, Hoganson, George, Hwu, Wuh-Liang, James, Philip, Kim, Sook, Korman, Stanley H., Lachmann, Robin, Levy, Harvey, Lindner, Martin, Lykopoulou, Lilia, Mayatepek, Ertan, Muntau, Ania, Okano, Yoshiyuki, Raymond, Kimiyo, Rubio-Gozalbo, Estela, Scholl-Buergi, Sabine, Schulze, Andreas, Singh, Rani, Stabler, Sally, Stuy, Mary, Thomas, Janet, Wagner, Conrad, Wilson, William G., Wortmann, Saskia, Yamamoto, Shigenori, Pao, Maryland, Blom, Henk J., MDL patientenzorg, Child Health, Chien, Yin-Hsiu, Abdenur, Jose E., Baronio, Federico, Bannick, Allison Anne, Corrales, Fernando, Couce, Maria, Donner, Markus G., Ficicioglu, Can, Freehauf, Cynthia, Frithiof, Deborah, Gotway, Garrett, Hirabayashi, Koichi, Hofstede, FC, Hoganson, George, Hwu, Wuh-Liang, James, Philip, Kim, Sook, Korman, Stanley H., Lachmann, Robin, Levy, Harvey, Lindner, Martin, Lykopoulou, Lilia, Mayatepek, Ertan, Muntau, Ania, Okano, Yoshiyuki, Raymond, Kimiyo, Rubio-Gozalbo, Estela, Scholl-Buergi, Sabine, Schulze, Andreas, Singh, Rani, Stabler, Sally, Stuy, Mary, Thomas, Janet, Wagner, Conrad, Wilson, William G., Wortmann, Saskia, Yamamoto, Shigenori, Pao, Maryland, and Blom, Henk J.

Published
2015

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