TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation 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.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.

Spastic ataxia associated with colour vision deficiency due to DDHD2 mutations

“…This pattern of cognitive impairment is in keeping with reported frontal cortical DDHD2 expression [1]. Furthermore, the role of the cerebellum in cognitive impairment is increasingly recognized [4] and in accordance with high cerebellar DDHD2 expression.…”

Identification of the SCA21 disease gene: remaining challenges and promising opportunities

“…Several SCA21 patients also presented with mild to severe cognitive impairment. Re-analysis of this same family has now yielded evidence of additional clinical features including delayed acquisition of cognitive and motor skills, mild to severe mental retardation, variable onset of clumsiness, and examples of very slow disease progression (Delplanque et al, 2014). Although cognitive impairment has been observed in a few other SCAs, this phenotype is remarkably consistent in the large SCA21 pedigree described in the current work.…”

“…The SCAs that belong to Harding's type I ADCA category are a very heterogeneous group of diseases, with highly pleiotropic phenotypes and complex pyramidal and extrapyramidal symptoms, including cognitive decline, motor neuron disease, neuropathy, and depression. In this month's issue of Brain, Delplanque and colleagues add another piece to the SCA puzzle by refining the clinical description and defining the genetic basis of SCA21 (Delplanque et al, 2014). SCA21 was initially identified by the very same group more than a decade ago (Vuillaume et al, 2002), and its genetic locus was erroneously mapped to chromosome 7.…”

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