SPTAN1 pathogenic mutations have been associated with a strikingly broad phenotypic range. Epileptic syndromes, intellectual impairment, and inherited motor neuropathy are all clinical manifestations. The function of SPTAN1 mutations in uncommon neurological diseases such as ataxia and spastic paraplegia was explored.
For a study, researchers screened 10,000 NGS datasets from two worldwide consortia and one local database, demonstrating the extent of international collaboration necessary to discover genes responsible for the uncommon illness. The detected SPTAN1 variations were modeled in silico.
They presented 22 individuals from 14 families who have five new SPTAN1 mutations. About 4 of the 6 individuals with cerebellar ataxia have a de novo SPTAN1 mutation, whereas the other two have a sporadic inheritance. One mutation (p.Lys2083del) was found in four patients in the cohort. About 2 individuals had new de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) that caused cerebellar ataxia, with one also having intellectual impairment and epilepsy. In addition, they found a recurrent missense mutation (p.Arg19Trp) in 15 individuals with spastic paraplegia from seven families, with a dominant inheritance pattern in four cases and a de novo origin in one. Around 1 other patient displays a complicated spastic ataxic phenotype due to a de novo missense mutation (p.Gln2205Pro). They showed that altered amino acids are positioned at critical interlinking locations, joining the three-helix bundle of a spectrin repeat, using protein modeling.
SPTAN1 is a potential gene for ataxia and spastic paraplegia, according to the findings. They proposed that disruption of the interlinking of spectrin helices may be a significant element of the pathomechanism for the mutations found in the investigation.