title: Linkage study and exome sequencing identify a BDP1 mutation associated with hereditary hearing loss.
abstract: Nonsyndromic Hereditary Hearing Loss is a common disorder accounting for at least 60% of prelingual deafness. GJB2 gene mutations, GJB6 deletion, and the A1555G mitochondrial mutation play a major role worldwide in causing deafness, but there is a high degree of genetic heterogeneity and many genes involved in deafness have not yet been identified. Therefore, there remains a need to search for new causative mutations. In this study, a combined strategy using both linkage analysis and sequencing identified a new mutation causing hearing loss. Linkage analysis identified a region of 40 Mb on chromosome 5q13 (LOD score 3.8) for which exome sequencing data revealed a mutation (c.7873 T>G leading to p.*2625Gluext*11) in the BDP1 gene (B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB) in patients from a consanguineous Qatari family of second degree, showing bilateral, post-lingual, sensorineural moderate to severe hearing impairment. The mutation disrupts the termination codon of the transcript resulting in an elongation of 11 residues of the BDP1 protein. This elongation does not contain any known motif and is not conserved across species. Immunohistochemistry studies carried out in the mouse inner ear showed Bdp1 expression within the endothelial cells in the stria vascularis, as well as in mesenchyme-derived cells surrounding the cochlear duct. The identification of the BDP1 mutation increases our knowledge of the molecular bases of Nonsyndromic Hereditary Hearing Loss and provides new opportunities for the diagnosis and treatment of this disease in the Qatari population.
authors: Department of Medical Sciences, University of Trieste, Trieste, Italy.
authors: Giorgia
authors: G
authors: Girotto
authors: Khalid
authors: K
authors: Abdulhadi
authors: Annalisa
authors: A
authors: Buniello
authors: Diego
authors: D
authors: Vozzi
authors: Danilo
authors: D
authors: Licastro
authors: Angela
authors: A
authors: d'Eustacchio
authors: Dragana
authors: D
authors: Vuckovic
authors: Moza Khalifa
authors: MK
authors: Alkowari
authors: Karen P
authors: KP
authors: Steel
authors: Ramin
authors: R
authors: Badii
authors: Paolo
authors: P
authors: Gasparini
mesh_terms: D000818:Animals; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics* / Q000378:metabolism; D003053:Cochlear Duct / Q000378:metabolism / Q000473:pathology; D000072259:Connexin 26; D017630:Connexins; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008040:Genetic Linkage; D006315:Hearing Loss, Functional / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D035361:Transcription Factor TFIIIB / Q000235:genetics* / Q000378:metabolism
chemical_list: C427472:BDP1 protein, human; D017630:Connexins; C000607042:GJB2 protein, human; D035361:Transcription Factor TFIIIB; D000072259:Connexin 26