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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.* ; Lochmüller, 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.*

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

Am. J. Hum. Genet. 108, 2006-2016 (2021)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Aaa+ Superfamily ; Atpase ; Spata5l1 ; Cerebral Palsy ; Epilepsy ; Intellectual Disability ; Movement Disorder ; Neurodevelopmental Disorder ; Sensorineural Hearing Loss; Renal-function; Loci
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 108, Issue: 10, Pages: 2006-2016 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants R00HL143036-02
Clinical and Translational Research Funding Program
JPB Foundation
NEI intramural funds
Ministry of Science, Research, and Art Baden-Wurttemberg
University of Tubingen
Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health)
Canada Foundation for Innovation
Canadian Institutes of Health Research and Muscular Dystrophy Canada
Canadian Institutes of Health Research
Telethon Undiagnosed Diseases Program (TUDP)
ItalianMinistry of Health
Fondazione Bambino Gesu
Foundation for Barnes-Jewish Hospital
NIH/National Center for Advancing Translational Sciences
Tenix Foundation
Hospital Research Foundation Mid-Career Fellowship
Channel 7 CRF Chair for the Prevention of Childhood Disability
Australian National Health and Medical Research Council Fellowship
Australian National Health and Medical Research Council
Cerebral Palsy Alliance Research Foundation Career Development Award
NHMRC Early Career Research Fellowship
National Institute for Health Research University College London Hospitals Biomedical Research Centre
Wellcome Trust
Cerebral PalsyAlliance Research Foundation