Validation and characterization of SPTAN1 mutations as a novel cause for hereditary cerebellar ataxia.

SPTAN1 (α-II-spectrin) is the sole α-spectrin subtype in the nervous system and has a critical function in neuronal development and homeostasis. Intriguingly, mutations in SPTAN1 display a strikingly high degree of phenotypical heterogeneity. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). We now have additional preliminary evidence that implicates SPTAN1 variants in both ataxia, Hereditary Spastic Paraplegia (HSP) as well as myopathy, highlighting the relevance of SPTAN1 mutations in rare neurological and (neuro)muscular diseases. In this project we will investigate the novel link between SPTAN1 mutations and ataxia phenotypes by: (1) investigating one specific recurrent variant; (2) identifying additional pathogenic variants using a multiplex PCR screening method and; (3) using patient-derived cells to investigate a.o. mRNA and protein expression levels. Doing so we aim to establish ataxia as a novel phenotype within SPTAN1 related diseases and explore fundamental cellular characteristics of ataxia associated SPTAN1 mutations.

Keywords:CLINICAL SPECTRUM, GENETIC DISEASE, GENETIC SCREENING, NEUROMUSCULAR DISEASES

Disciplines:Neurological and neuromuscular diseases