title: Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease.
abstract: Meniere's disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD.
authors.affiliation: Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research - Pfizer/University of Granada/Junta de Andalucía, PTS, Granada 18016, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Requena
authors.affiliation: Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research - Pfizer/University of Granada/Junta de Andalucía, PTS, Granada 18016, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cabrera
authors.affiliation: Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research - Pfizer/University of Granada/Junta de Andalucía, PTS, Granada 18016, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martín-Sierra
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA and.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Price
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA and.
authors.forename: Anna
authors.initials: A
authors.lastname: Lysakowski
authors.affiliation: Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research - Pfizer/University of Granada/Junta de Andalucía, PTS, Granada 18016, Spain, Department of Otolaryngology, Hospital de Poniente, El Ejido, Almería 04700, Spain antonio.lopezescamez@genyo.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Lopez-Escamez
mesh_terms: D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D049029:Dystrophin-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008575:Meniere Disease / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats
chemical_list: C490915:DTNA protein, human; D049029:Dystrophin-Associated Proteins; C000601377:FAM136A protein, human; D024101:Mitochondrial Proteins; D009479:Neuropeptides