TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment

TL;DR

Mutations in the TMEM240 gene cause spinocerebellar ataxia 21, a neurodegenerative disorder characterized by cerebellar ataxia and severe cognitive impairment, with new mutations identified in multiple families.

Contribution

This study identifies TMEM240 mutations as the cause of spinocerebellar ataxia 21 and expands the mutation spectrum associated with this disorder.

Findings

TMEM240 mutations are linked to SCA21 in multiple families.

The identified mutations include missense and stop mutations.

SCA21 is associated with early-onset and severe cognitive impairment.

Abstract

Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C4T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C4T/p.P170L, c.239C4T/p.T80M, c.346C4T/p.R116C, c.445G4A/p.E149K, c.511C4T/p.R171W), and a stop mutation (c.489C4G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.