title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
abstract: 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.
authors.affiliation: Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Ersan
authors.initials: E
authors.lastname: Kalay
authors.forename: Muhammad
authors.initials: M
authors.lastname: Tariq
authors.forename: Theo
authors.initials: T
authors.lastname: Peters
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Refik
authors.initials: R
authors.lastname: Caylan
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Henk A
authors.initials: HA
authors.lastname: Spierenburg
authors.forename: Erol
authors.initials: E
authors.lastname: Eyupoglu
authors.forename: Angelien
authors.initials: A
authors.lastname: Heister
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Elif
authors.initials: E
authors.lastname: Bahat
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Selcuk
authors.initials: S
authors.lastname: Arslan
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Ahmet
authors.initials: A
authors.lastname: Karaguzel
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000595:Amino Acid Sequence; D002883:Chromosomes, Human, Pair 14; D004252:DNA Mutational Analysis; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism; D005260:Female; D020440:Gene Duplication; D005808:Genes, Recessive; D008040:Genetic Linkage; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: C490918:ESRRB protein, human; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen