Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome

Abstract

SPTBN1 encodes βII-spectrin, the ubiquitously expressed member of the β-spectrin family that forms micrometer-scale networks associated with plasma membranes. βII-spectrin is abundantly expressed in the brain, where it is essential for neuronal development and connectivity. Mice deficient in neuronal βII-spectrin expression have defects in cortical organization, global developmental delay, dysmorphisms, and behavioral deficiencies of corresponding severity. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous variants in this gene may also present with measurable compromise of neural development and function. Here we report the identification of heterozygous SPTBN1 variants in 29 individuals who present with global 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 loss-of-function, gain-of-function, and dominant negative effects that affect protein stability, disrupt binding to key protein partners, and affect cytoskeleton organization and dynamics. Our studies define the genetic basis of this new neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and neural development, and underscore the critical role of βII-spectrin in the central nervous system.

Putting the axonal periodic scaffold in order

“…New perturbation strategies with better molecular, spatial and temporal specificity such as optically-driven inhibitors will allow to dissect the role of the MPS in axonal physiological processes, before zooming out to assess the consequences on neuronal connectivity and information processing. Finally, potential dysfunctions of the MPS in neuropsychiatric diseases, from spectrinopathies [68,69] to Alzheimer's disease, remain to be explored.…”

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 3A, 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 SPTBN1 , which encodes βII-spectrin, cause a neurodevelopmental syndrome associated with deficits in cortical connectivity ( Cousin et al, 2020 ), 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 3A during GC collapse.…”

Outer hair cell function is normal in βV spectrin knockout mice

“…In Spnb5, these sites are located at aa 20-124 (CH1) and aa 143-247 (CH2) and encoded by the transcript well before the RNAscope in situ probe binding sites. In other beta spectrins, loss of function mutations occur within the CH1 and CH2 actin binding domains (Cousin et al, 2020). While it is still possible that there are mRNA transcripts that are shorter with in-frame methionine start sites, these transcripts would not be expected to produce a functional protein in lieu of it lacking the CH1 and CH2 actin binding domains (there are, for instance, 43 in-frame methionine codons, 19 of which also contain consensus Kozak sequences, that lie downstream of the in situ hybridization probe binding sites).…”