Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35 by Collin Rob W J, Kalay Ersan, Tariq Muhammad, Peters Theo, van der Zwaag Bert, Venselaar Hanka, Oostrik Jaap, Lee Kwanghyuk, Ahmed Zubair M, Caylan Refik, Li Yun, Spierenburg Henk A, Eyupoglu Erol, Heister Angelien, Riazuddin Saima, Bahat Elif, Ansar Muhammad, Arslan Selcuk, Wollnik Bernd, Brunner Han G, Cremers Cor W R J, Karaguzel Ahmet, Ahmad Wasim, Cremers Frans P M, Vriend Gert, Friedman Thomas B, Riazuddin Sheikh, Leal Suzanne M, Kremer Hannie in American journal of human genetics (2008).

[PMID: 18179891] PubMed


In a large consanguineous family of Turkish origin, genome-wide homozygosity mapping revealed a locus for recessive nonsyndromic hearing impairment on chromosome 14q24.3-q34.12. Fine mapping with microsatellite markers defined the critical linkage interval to a 18.7 cM region flanked by markers D14S53 and D14S1015. This region partially overlapped with the DFNB35 locus. Mutation analysis of ESRRB, a candidate gene in the overlapping region, revealed a homozygous 7 bp duplication in exon 8 in all affected individuals. This duplication results in a frame shift and premature stop codon. Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family and in three other DFNB35-linked consanguineous families from Pakistan revealed four missense mutations. ESRRB encodes the estrogen-related receptor beta protein, and one of the substitutions (p.A110V) is located in the DNA-binding domain of ESRRB, whereas the other three are substitutions (p.L320P, p.V342L, and p.L347P) located within the ligand-binding domain. Molecular modeling of this nuclear receptor showed that the missense mutations are likely to affect the structure and stability of these domains. RNA in situ hybridization in mice revealed that Esrrb is expressed during inner-ear development, whereas immunohistochemical analysis showed that ESRRB is present postnatally in the cochlea. Our data indicate that ESRRB is essential for inner-ear development and function. To our knowledge, this is the first report of pathogenic mutations of an estrogen-related receptor gene.

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