Loss of Function SPTAN1 Variants Result in Ataxia and Intellectual Disability.

Abstract

SPTAN1 mutations have been reported in association with autosomal dominant early infantile epileptic encephalopathy 5. Individuals present with early-onset seizures and profound intellectual disability. Recent reports suggest a wider spectrum with later-onset seizures and milder developmental delay. Here we describe two patients with loss-of-function variants in SPTAN1. One patient has ataxia and mild intellectual disability stemming from a de novo homozygous p.(Gln1448Pro) variant associated with uniparental disomy 9. The second patient, carrying a heterozygous p.(Asn1839del) allele, exhibits more substantial motor issues, developmental delay, and seizures. Ectopically expressed wild-type or variant-containing forms of sptan1 in zebrafish indicate both variants create loss-of-function alleles, with the p.(Gln1448Pro) likely being hypomorphic. This conclusion is supported by reduced protein abundance and localization of Sptan1 variants in axons of developing embryos. Further, unlike wild-type sptan1, analysis of the p.(Gln1448Pro) variant showed it failed to restore voltage-gated sodium channel localization in sptan1-null axons. Additional behavioral analyses show supplementation with the amino acid D-aspartate improved motility in sptan1-null zebrafish, supporting its use for α-II spectrin-associated motor dysfunction.