Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.
Nat Genet
; 53(7): 1006-1021, 2021 07.
Article
in En
| MEDLINE
| ID: mdl-34211179
ABSTRACT
SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-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 ßII-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 ßII-spectrin in the central nervous system.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Variation
/
Spectrin
/
Genetic Predisposition to Disease
/
Neurodevelopmental Disorders
/
Genes, Dominant
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2021
Document type:
Article
Affiliation country:
Estados Unidos