  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.
