Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

Abstract

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 present with measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals who present 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 βIIspectrin 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. Spectrins are ubiquitously expressed, elongated polypeptides that bind membrane lipids and ankyrins to line the plasma membrane 1,2 . The spectrin meshwork is formed by heterodimeric units of α-spectrin and β-spectrin assembled side-to-side in antiparallel fashion, which then form head-to-head tetramers that crosslink F-actin to form spectrin-actin arrays 1,2 . Mammalian neurons express the most diverse repertoire of spectrins, which Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms *

Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

“…Five affected individuals had coding variants in syndromic ASD genes: JC-50-3 in KMT2C , JC-57-3 in ZNF292 , JC-60-3 in SYNE1 , MC-04-3 in SPTBN1 , and MC-17-3 in SCN1A . Proband MC-04-3 presented with ASD, speech abnormalities, and developmental delay, in line with phenotypes of patients with pathogenic SPTBN1 mutations (MIM #619475) 43 , 44 . In addition to ASD, proband MC-17-3 presented with epilepsy, the characteristic phenotype in patients with SCN1A loss of function mutations.…”

Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor sema 3A

“…Interestingly, GCs of neurons lacking the F-actin and AnkB partner βII-spectrin respond normally to Sema 3 A, which indicates that βII-spectrin is not required for Sema 3A-induced GC collapse. However, given βII-spectrin’s role in the development and wiring of axons in mouse brains ( Galiano et al, 2012 ; Lorenzo et al, 2019 ) and the recent identification that pathogenic variants in the βII-spectrin encoding gene SPTBN1 cause a neurodevelopmental syndrome associated with deficits in cortical connectivity ( Cousin et al, 2021 ), we cannot rule out its involvement in axonal guidance through alternative mechanisms. Interestingly, although AnkB440 binding to microtubules suppresses branch initiation, loss of this interaction does not affect the response to Sema 3 A during GC collapse.…”

Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans

“…31 Very recently, dominant variants in βII-spectrin SPTBN1 were associated with a neurodevelopmental syndrome. 32 Thus, the adducin-β-spectrin complex plays an essential role in the mouse and human brain development.…”