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TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy.

ABSTRACT: Nonsyndromic autosomal-recessive optic neuropathies are rare conditions of unknown genetic and molecular origin. Using an approach of whole-genome homozygosity mapping and positional cloning, we have identified the first gene, to our knowledge, responsible for this condition, TMEM126A, in a large multiplex inbred Algerian family and subsequently in three other families originating from the Maghreb. TMEM126A is conserved in higher eukaryotes and encodes a transmembrane mitochondrial protein of unknown function, supporting the view that mitochondrial dysfunction may be a hallmark of inherited optic neuropathies including isolated autosomal-recessive forms.

SUBMITTER: Hanein S

PROVIDER: S-EPMC2667974 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy.

Hanein Sylvain S Perrault Isabelle I Roche Olivier O Gerber Sylvie S Khadom Noman N Rio Marlene M Boddaert Nathalie N Jean-Pierre Marc M Brahimi Nora N Serre Valérie V Chretien Dominique D Delphin Nathalie N Fares-Taie Lucas L Lachheb Sahran S Rotig Agnès A Meire Françoise F Munnich Arnold A Dufier Jean-Louis JL Kaplan Josseline J Rozet Jean-Michel JM

American journal of human genetics 20090326 4

Nonsyndromic autosomal-recessive optic neuropathies are rare conditions of unknown genetic and molecular origin. Using an approach of whole-genome homozygosity mapping and positional cloning, we have identified the first gene, to our knowledge, responsible for this condition, TMEM126A, in a large multiplex inbred Algerian family and subsequently in three other families originating from the Maghreb. TMEM126A is conserved in higher eukaryotes and encodes a transmembrane mitochondrial protein of un ...[more]

PMID: 19327736

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Project description:To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy and auditory neuropathy in a consanguineous family with two affected children.Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then screened for mutations by direct sequencing.Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1-11q22.3, which was confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A (TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X).We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently described disorder.

Project description:BackgroundReports on autosomal recessive optic atrophy (arOA) are sparse and so far, only one gene has been specifically associated with non-syndromic arOA, namely TMEM126A. To date, all reports of pathogenic TMEM126A variants are from affected individuals of Maghrebian origin, who all carry an identical nonsense variant. Here we report two novel variants in the TMEM126A gene from non-Maghreb individuals, both found in affected individuals with an arOA phenotype.Case presentationWe report three affected individuals from two families. The proband of family A, a 24-year-old Turkish woman, was diagnosed with visual loss in early childhood but a diagnosis of optic atrophy was only made at 14 years. A diagnostic gene panel revealed a splice donor variant (c.86 + 2 T > C) in homozygous state in the TMEM126A gene. Analysis of this variant based on RNA from whole blood revealed a single aberrant transcript lacking exon 2, presumably representing a functional null allele. Two siblings from family B, a 16-year old Iraqi girl and her 14-year old brother, were diagnosed with optic atrophy in early childhood. A missense variant p.(S36 L) in the TMEM126A gene was identified in homozygous state in a gene panel-based diagnostic setting in both siblings. This missense variant is ultra rare in the general population, affects a highly evolutionarily conserved amino acid and segregates with the disease within the family. The three probands reported in this study had a relatively mild clinical course without any evidence of a syndromic (e.g. neurological) comorbidity, which is in line with previous studies.ConclusionsWe provide additional evidence for the implication of biallelic pathogenic TMEM126A variants in arOA. Our findings extend both the mutational spectrum and geographic presence of TMEM126A in arOA. Screening of the entire gene should be considered in affected individuals presenting with features resembling arOA and also from non-Maghrebian descent.

Dataset Information

TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy.

Publications

TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy.

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