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DOI 10.1016/j.ajhg.2021.08.003

Медицинская библиотека · American journal of human genetics · 2021

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

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

Клинический случайСтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: Richard Elodie M, Bakhtiari Somayeh, Marsh Ashley P L, Kaiyrzhanov Rauan, Wagner Matias, Shetty Sheetal, Pagnozzi Alex, Nordlie Sandra M, Guida Brandon S, Cornejo Patricia, Magee Helen, Liu James, Norton Bethany Y, Webster Richard I, Worgan Lisa, Hakonarson Hakon, Li Jiankang, Guo Yiran, Jain Mahim, Blesson Alyssa, Rodan Lance H, Abbott Mary-Alice, Comi Anne, Cohen Julie S, Alhaddad Bader, Meitinger Thomas, Lenz Dominic, Ziegler Andreas, Kotzaeridou Urania, Brunet Theresa, Chassevent Anna, Smith-Hicks Constance, Ekstein Joseph, Weiden Tzvi, Hahn Andreas, Zharkinbekova Nazira, Turnpenny Peter, Tucci Arianna, Yelton Melissa, Horvath Rita, Gungor Serdal, Hiz Semra, Oktay Yavuz, Lochmuller Hanns, Zollino Marcella, Morleo Manuela, Marangi Giuseppe, Nigro Vincenzo, Torella Annalaura, Pinelli Michele, Amenta Simona, Husain Ralf A, Grossmann Benita, Rapp Marion, Steen Claudia, Marquardt Iris, Grimmel Mona, Grasshoff Ute, Korenke G Christoph, Owczarek-Lipska Marta, Neidhardt John, Radio Francesca Clementina, Mancini Cecilia, Claps Sepulveda Dianela Judith, McWalter Kirsty, Begtrup Amber, Crunk Amy, Guillen Sacoto Maria J, Person Richard, Schnur Rhonda E, Mancardi Maria Margherita, Kreuder Florian, Striano Pasquale, Zara Federico, Chung Wendy K, Marks Warren A, van Eyk Clare L, Webber Dani L, Corbett Mark A, Harper Kelly, Berry Jesia G, MacLennan Alastair H, Gecz Jozef, Tartaglia Marco, Salpietro Vincenzo, Christodoulou John, Kaslin Jan, Padilla-Lopez Sergio, Bilguvar Kaya, Munchau Alexander, Ahmed Zubair M, Hufnagel Robert B, Fahey Michael C, Maroofian Reza, Houlden Henry, Sticht Heinrich, Mane Shrikant M, Rad Aboulfazl, Vona Barbara, Jin Sheng Chih, Haack Tobias B, Makowski Christine, Hirsch Yoel, Riazuddin Saima, Kruer Michael C. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.. American journal of human genetics. 2021. DOI: 10.1016/j.ajhg.2021.08.003.

Предметные рубрики MeSH

ATPases Associated with Diverse Cellular ActivitiesAdolescentAdultAllelesAnimalsCerebral PalsyChild, PreschoolEpilepsyFemaleGenetic Predisposition to DiseaseGenetic VariationHearing LossHumansInfantInfant, NewbornIntellectual DisabilityMaleMuscle SpasticityRatsYoung Adult
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