Mutations of ESRRB Encoding Estrogen-Related Receptor Beta Cause Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB35

Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.99). 02/2008; 82(1):125-38. DOI: 10.1016/j.ajhg.2007.09.008
Source: PubMed

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.

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Available from: Theo A Peters, Jul 28, 2015
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    • "In particular, two ESRRB mutations, namely, p.Val342Leu and p.Leu347Pro [2], also occur within α-helix 8. Both substitutions are predicted to disrupt hydrophobic interactions of α-helix 8 with other helices, thus resulting in conformational change and decreased stability of the LBD [2]. Mutations in α-helix 8 that decrease ligand-binding affinity have been identified in other nuclear receptor proteins, ESR1 and HNF4α, which have structures similar to ESRRB [16] [17]. "
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    ABSTRACT: Mutations in the estrogen-related receptor beta (ESRRB) gene is the underlying cause of autosomal recessive nonsyndromic hearing impairment (ARNSHI) due to the DFNB35 locus which maps to 14q24.3. A genome scan of a large consanguineous Pakistani pedigree with ARNSHI established linkage with a maximum multipoint LOD score of 4.2 to the 14q24 region and the region of homozygosity contained the ESRRB gene. Sequencing of the ESRRB gene using DNA samples from hearing-impaired family members uncovered a novel three-nucleotide deletion c.1018_1020delGAG (p.Glu340del). The deletion segregates with hearing impairment in the pedigree and was not observed in 500 control chromosomes. The deletion of glutamic acid residue occurs in the ligand-binding domain of ESRRB protein. It is expected that the deletion affects the ligand-binding activity of the domain in ESRRB, which leads to the ARNSHI.
    09/2011; 2011:368915. DOI:10.4061/2011/368915
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    • "Nonsyndromic hearing impairment is genetically extremely heterogeneous; already more than 60 DFNB loci de Heer et al. Audiol Neurotol 2011;16:93–105 and 30 of the causative genes have been identified [Ahmed et al., 2008; Collin et al., 2008b; van Camp and Smith, 2008]. Different mutations in the transmembrane channellike 1 gene (TMC1) can cause prelingual autosomal recessive profound deafness (DFNB7/11) as well as postlingual progressive autosomal dominant (DFNA36) sensorineural hearing loss [Kurima et al., 2002]. "
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    ABSTRACT: In a Dutch family with autosomal recessive hearing loss, genome-wide single-nucleotide polymorphism analysis mapped the genetic defect to the DFNB7/11 locus. A novel homozygous A-to-G change in the TMC1 gene was detected near the splice donor site of intron 19 (c.1763+3A→G) segregating with the hearing loss in this family. One of the 6 transmembrane domains and the actual TMC channel domain are predicted to be absent in the mutant protein. The sensorineural hearing impairment in this DFNB7/11 family has a postlingual onset. Audiometric analysis initially showed a steeply downward-sloping threshold configuration. The progressive phenotype in this family resembles the phenotype previously described for families with dominant TMC1 mutations (DFNA36) rather than that of families with recessive TMC1 mutations (DFNB7/11) which invariably cause severe-to-profound prelingual hearing impairment.
    Audiology and Neurotology 01/2011; 16(2):93-105. DOI:10.1159/000313282 · 1.85 Impact Factor
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    • "Sequence analysis revealed four mis-sense mutations of the estrogen-related receptor beta (ESRRB) gene leading to autosomal-recessive non-syndromic hearing impairment (Collin et al. 2008). Experimental results indicated that ESRRB is essential for inner-ear development and function. "
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    ABSTRACT: Homology modelling is normally the technique of choice when experimental structure data are not available but three-dimensional coordinates are needed, for example, to aid with detailed interpretation of results of spectroscopic studies. Herein, the state of the art of homology modelling will be described in the light of a series of recent developments, and an overview will be given of the problems and opportunities encountered in this field. The major topic, the accuracy and precision of homology models, will be discussed extensively due to its influence on the reliability of conclusions drawn from the combination of homology models and spectroscopic data. Three real-world examples will illustrate how both homology modelling and spectroscopy can be beneficial for (bio)medical research.
    Biophysics of Structure and Mechanism 09/2009; 39(4):551-63. DOI:10.1007/s00249-009-0531-0 · 2.47 Impact Factor
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