Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

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.

Generation of an induced pluripotent stem cell line (UNCCi002-A) from a healthy donor using a non-integration system to study Cerebral Cavernous Malformation (CCM).

The generation of induced pluripotent stem cells (iPSCs) from healthy individuals is an invaluable resource as reference control in disease modeling and drug discovery. This paper details the reprogramming of peripheral blood mononuclear cells (PBMCs) isolated from a healthy 27 years-old male using non-integration technology. The derived iPSCs displayed typical pluripotent stem cell morphology, the capacity to differentiate into the three germ layers, and normal karyotype. This iPSC line will be used as a reference control to study the Cerebral Cavernous Malformation disease mechanism.