title: Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Tee
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Fatimah
authors.initials: F
authors.lastname: Rahman
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Linda M
authors.initials: LM
authors.lastname: Luxon
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000293:Adolescent; D001301:Audiometry, Pure-Tone; D001304:Auditory Diseases, Central / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D001309:Auditory Threshold / Q000502:physiology; D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005074:Evoked Potentials, Visual / Q000502:physiology; D005260:Female; D005654:Fundus Oculi; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009412:Nerve Fibers / Q000473:pathology; D015418:Optic Atrophies, Hereditary / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology; D010375:Pedigree; D055351:Retinal Neurons / Q000473:pathology; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C549198:TMEM126A protein, human
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