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Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.

ABSTRACT: To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome.Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry.In family 1, affected individuals were compound heterozygous for chromosome 10 open reading frame 2 (C10orf2) p.Arg391His and p.Asn585Ser. In family 2, affected individuals were compound heterozygous for C10orf2 p.Trp441Gly and p.Val507Ile. C10orf2 encodes Twinkle, a primase-helicase essential for replication of mitochondrial DNA. Conservation and structural modeling support the causality of the mutations. Twinkle is known also to harbor multiple mutations, nearly all missenses, leading to dominant progressive external ophthalmoplegia type 3 and to recessive mitochondrial DNA depletion syndrome 7, also known as infantile-onset spinocerebellar ataxia.Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.

SUBMITTER: Morino H

PROVIDER: S-EPMC4248451 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.

Morino Hiroyuki H Pierce Sarah B SB Matsuda Yukiko Y Walsh Tom T Ohsawa Ryosuke R Newby Marta M Hiraki-Kamon Keiko K Kuramochi Masahito M Lee Ming K MK Klevit Rachel E RE Martin Alan A Maruyama Hirofumi H King Mary-Claire MC Kawakami Hideshi H

Neurology 20141029 22

<h4>Objective</h4>To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome.<h4>Methods</h4>Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry.<h4>Results</h4>In family 1, affected individ ...[more]

PMID: 25355836

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Project description:BackgroundPerrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations.MethodsAffected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene.ResultsThree siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern.ConclusionsOur results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.

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Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.

Publications

Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.

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