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Cousin, M.A.* ; Creighton, B.A.* ; Breau, K.A.* ; Spillmann, R.C.* ; Torti, E.* ; Dontu, S.* ; Tripathi, S.* ; Ajit, D.* ; Edwards, R.J.* ; Afriyie, S.* ; Bay, J.C.* ; Harper, K.M.* ; Beltran, A.A.* ; Munoz, L.J.* ; Falcon Rodriguez, L.* ; Stankewich, M.C.* ; Person, R.E.* ; Si, Y.* ; Normand, E.A.* ; Blevins, A.* ; May, A.S.* ; Bier, L.* ; Aggarwal, V.* ; Mancini, G.M.S.* ; van Slegtenhorst, M.A.* ; Cremer, K.* ; Becker, J.* ; Engels, H.* ; Aretz, S.* ; MacKenzie, J.J.* ; Brilstra, E.* ; van Gassen, K.L.I.* ; van Jaarsveld, R.H.* ; Oegema, R.* ; Parsons, G.M.* ; Mark, P.* ; Helbig, I.* ; McKeown, S.E.* ; Stratton, R.* ; Cogné, B.* ; Isidor, B.* ; Cacheiro, P.* ; Smedley, D.* ; Firth, H.V.* ; Bierhals, T.* ; Kloth, K.* ; Weiss, D.* ; Fairley, C.* ; Shieh, J.T.* ; Kritzer, A.* ; Jayakar, P.* ; Kurtz-Nelson, E.* ; Bernier, R.A.* ; Wang, T.* ; Eichler, E.E.* ; van de Laar, I.M.B.H.* ; McConkie-Rosell, A.* ; McDonald, M.T.* ; Kemppainen, J.* ; Lanpher, B.C.* ; Schultz-Rogers, L.E.* ; Gunderson, L.B.* ; Pichurin, P.N.* ; Yoon, G.* ; Zech, M. ; Jech, R.* ; Winkelmann, J. ; Beltran, A.S.* ; Zimmermann, M.T.* ; Temple, B.* ; Moy, S.S.* ; Klee, E.W.* ; Tan, Q.K.* ; Lorenzo, D.N.*

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

Nat. Genet. 53, 1006-1021 (2021)
Open Access Green as soon as Postprint is submitted to ZB.
SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Calponin Homology Domains; West Syndrome; Spinocerebellar Ataxia; Ii Spectrin; Alpha-ii; Actin; Mutations; Sptan1; Hypomyelination; Identification
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 53, Issue: 7, Pages: 1006-1021 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants U.S. Department of Health & Human Services | National Institutes of Health (NIH)