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

Brain. 2014 Oct;137(Pt 10):2657-63. doi: 10.1093/brain/awu202. Epub 2014 Jul 28.


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.509C>T/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.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/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.

Keywords: TMEM240; exome; spinocerebellar ataxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Amino Acid Sequence
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 1 / genetics
  • Cognition Disorders / genetics*
  • Cognition Disorders / psychology
  • Cohort Studies
  • Conserved Sequence
  • DNA Mutational Analysis
  • Exome / genetics
  • Female
  • France
  • Genetic Linkage
  • Humans
  • Infant
  • Intellectual Disability / genetics*
  • Intellectual Disability / psychology
  • Intelligence Tests
  • Introns
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Molecular Sequence Data
  • Mutation / physiology*
  • Neuropsychological Tests
  • Pedigree
  • Polymerase Chain Reaction
  • Spinocerebellar Degenerations / genetics*
  • Spinocerebellar Degenerations / pathology
  • Spinocerebellar Degenerations / psychology
  • Young Adult


  • Membrane Proteins
  • TMEM240 protein, human

Supplementary concepts

  • Spinocerebellar ataxia 21