Identification of a Novel Recessive Ataxia Gene.

Abstract

While the genes involved in most forms of sporadic or recessive ataxia with mental retardation are still unknown, exome sequencing is a promising tool to identify novel genes in rare disorders. Previously, two siblings in a consanguineous Turkish family were reported, who presented with a non- progressive ataxia syndrome including congenital truncal and extremity ataxia, cerebellar hypoplasia, hypotonia, developmental delay, mental retardation and nystagmus. After exome sequencing and filtering by homozygosity, we identified a homozygous mutation at the invariant +1 position (c. 964+1 G>A) in intron 9 of the CWF19L1 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in >6,500 European and African American individuals and 200 Turkish control DNAs. In lymphoblastoid cell lines from affected individuals, the mutation causes exon skipping, reduction in mRNA levels, and protein loss. Morpholino- mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved CWF19L1, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities. Preliminary data suggests this protein is expressed in a tissue-specific manner and that this protein is localized in the nucleus. Our results suggest that we have identified a novel cause of recessive ataxia and developmental delay.