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Publication : Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

First Author  Cousin MA Year  2021
Journal  Nat Genet Volume  53
Issue  7 Pages  1006-1021
PubMed ID  34211179 Mgi Jnum  J:322307
Mgi Id  MGI:6742151 Doi  10.1038/s41588-021-00886-z
Citation  Cousin MA, et al. (2021) Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nat Genet 53(7):1006-1021
abstractText  SPTBN1 encodes betaII-spectrin, the ubiquitously expressed beta-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal betaII-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 betaII-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 betaII-spectrin in the central nervous system.
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