Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
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.
Collin
Rob W J
RW
Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
Kalay
Ersan
E
Tariq
Muhammad
M
Peters
Theo
T
van der Zwaag
Bert
B
Venselaar
Hanka
H
Oostrik
Jaap
J
Lee
Kwanghyuk
K
Ahmed
Zubair M
ZM
Caylan
Refik
R
Li
Yun
Y
Spierenburg
Henk A
HA
Eyupoglu
Erol
E
Heister
Angelien
A
Riazuddin
Saima
S
Bahat
Elif
E
Ansar
Muhammad
M
Arslan
Selcuk
S
Wollnik
Bernd
B
Brunner
Han G
HG
Cremers
Cor W R J
CW
Karaguzel
Ahmet
A
Ahmad
Wasim
W
Cremers
Frans P M
FP
Vriend
Gert
G
Friedman
Thomas B
TB
Riazuddin
Sheikh
S
Leal
Suzanne M
SM
Kremer
Hannie
H
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
C490918:ESRRB protein, human; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen