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SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.

ABSTRACT: BACKGROUND:Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with high clinical and genetic heterogeneity. In most cases, the cerebellar ataxia is not pure, and complicating clinical features such as pyramidal signs or extraneurological features are found. OBJECTIVE:To identify the genetic origin of the cerebellar ataxia for 3 consanguineous North African families presenting with ARCA. METHODS:Genome-wide high-density SNP genotyping and whole-exome sequencing were performed followed by Sanger sequencing for mutation confirmation. RESULTS:Two variants were identified in SLC25A46. Mutations in this gene have been previously associated with Charcot-Marie-Tooth type 2 and optic atrophy. While the previously reported variant p.Arg340Cys seems to be consistently associated with the same clinical features such as childhood onset, optic atrophy, gait and speech difficulties, and wasting of the lower limbs, the patient with the novel mutation p.Trp160Ser did not present with optic atrophy and his ocular abnormalities were limited to nystagmus and saccadic pursuit. CONCLUSION:In this study, we report a novel variant (p.Trp160Ser) in SLC25A46 and we broaden the phenotypic spectrum associated with mutations in SLC25A46.

SUBMITTER: Hammer MB

PROVIDER: S-EPMC5540751 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.

Hammer Monia B MB Ding Jinhui J Mochel Fanny F Eleuch-Fayache Ghada G Charles Perrine P Coutelier Marie M Gibbs J Raphael JR Arepalli Sampath K SK Chong Sean B SB Hernandez Dena G DG Majounie Elisa E Clipman Steven S Bouhlal Yosr Y Nehdi Houda H Brice Alexis A Hentati Faycal F Stevanin Giovanni G Amouri Rim R Durr Alexandra A Singleton Andrew B AB

Neuro-degenerative diseases 20170531 4-5

<h4>Background</h4>Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with high clinical and genetic heterogeneity. In most cases, the cerebellar ataxia is not pure, and complicating clinical features such as pyramidal signs or extraneurological features are found.<h4>Objective</h4>To identify the genetic origin of the cerebellar ataxia for 3 consanguineous North African families presenting with ARCA.<h4>Methods</h4>Genome-wide high-density SNP genot ...[more]

PMID: 28558379

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Project description:Background and objectivesThe term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the ANO10 gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic spectrum among patients, even among those with the same or similar genetic variants. This study aimed to characterize the molecular consequences of variants in ANO10 and determine their pathologic significance in patients diagnosed with SCAR10.MethodsWe presented 4 patients from 4 families diagnosed with spinocerebellar ataxia with potential pathogenic variants in the ANO10 gene. Patients underwent either clinical whole-exome sequencing or screening of a panel of known neuromuscular disease genes. Effects on splicing were studied using reverse transcriptase PCR to analyze complementary DNA. Western blots were used to examine protein expression.ResultsOne individual who presented clinically at a much earlier age than typical was homozygous for an ANO10 variant (c.1864A > G [p.Met622Val]) that produces 2 transcription products by altering an exonic enhancer site. Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in ANO10 (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein. Both these variants have not yet been associated with SCAR10. The remaining patient was found to have compound heterozygous variants in ANO10 previously associated with SCAR10 (c.132dupA [p.Asp45Argfs*9] and c.1537T > C [p.Cys513Arg]).DiscussionWe presented rare pathogenic variants adding to the growing list of ANO10 variants associated with SCAR10. In addition, we described an individual with a much earlier age at onset than usually associated with ANO10 variants. This expands the phenotypic and allelic heterogeneity of ANO10-associated ARCA.

Dataset Information

SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.

Publications

SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.

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