Alternative titles; symbols
HGNC Approved Gene Symbol: ESRRB
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:76,310,777-76,501,837 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Deafness, autosomal recessive 35 | 608565 | Autosomal recessive | 3 |
See estrogen-related receptor-alpha (ESRRA; 601998). Giguere et al. (1988) first identified ESRRB as a gene whose product is similar to the estrogen receptor (133430).
Luo et al. (1997) demonstrated that mouse Esrrb plays an essential role in placental development: homozygous null Esrrb mutants die in midgestation due to abnormal development of the chorion and defective diploid trophoblast proliferation. Its embryonic lethal phenotype prevented the identification of potential roles for ESRRB in postnatal physiology.
Collin et al. (2008) found by RNA in situ hybridization in mice that Esrrb is expressed during inner ear development, whereas immunohistochemical analyses showed that ESRRB is present postnatally in the human cochlea. The data indicated that ESRRB is essential for inner ear development and function.
Doege et al. (2012) described an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as NANOG (607937) and ESRRB. By day 4 after transduction with pluripotency factors OCT4 (164177), SOX2 (184429), KLF4 (602253), and MYC (190080) (together referred to as OSKM), 2 epigenetic modification factors necessary for induced pluripotent stem cell (iPSC) generation, namely, PARP1 (173870) and TET2 (612839), were recruited to the NANOG and ESRRB loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: PARP1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas TET2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC. Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, Doege et al. (2012) concluded that their data, and also studies of TET2-mutant human tumor cells, argued in favor of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, PARP1 and TET2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas PARP1 induction further promotes accessibility to the OCT4 reprogramming factor. Doege et al. (2012) concluded that their findings suggested that PARP1 and TET2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.
Sladek et al. (1997) mapped the ESRRB gene to 14q24.3 by fluorescence in situ hybridization.
In a large consanguineous family of Turkish origin, Collin et al. (2008) used genomewide homozygosity mapping to demonstrate a locus for recessive nonsyndromic hearing impairment on 14q24.3-q34.12. Fine mapping with microsatellite markers defined a critical linkage interval to an 18.7-cM region. This region partially overlapped with the DFNB35 locus (608565). Mutation analysis of ESRRB, a candidate gene in the overlapping region, revealed a homozygous 7-bp duplication in exon 8 in all affected individuals (602167.0001). Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family and in 3 other DFNB35-linked consanguineous families from Pakistan revealed 4 missense mutations. One of the substitutions (A110V; 602167.0002) was located in the DNA-binding domain of ESRRB, whereas the other 3 were substitutions in the ligand-binding domain. Molecular modeling of this receptor showed that the missense mutations were likely to affect the structure and stability of these domains. This was thought to be the first report of pathogenic mutations of an estrogen-related receptor gene.
In a large consanguineous family of Turkish origin, Collin et al. (2008) found that autosomal recessive nonsyndromic hearing loss (DFNB35; 608565) was related to a homozygous 7-bp duplication in exon 8 of the ESRRB gene. The duplication, 1018_1024dupGAGTTTG, was predicted to change the reading frame and cause premature termination of the protein (Val342GlyfsTer44).
In a consanguineous family from Pakistan, Collin et al. (2008) found that nonsyndromic hearing impairment (DFNB35; 608565) was caused by a homozygous 329C-T transition in the ESRRB gene that resulted in an ala110-to-val substitution (A110V) in the DNA-binding domain.
In the original family with autosomal recessive deafness-35 (DFNB35; 608565) reported by Ansar et al. (2003), Collin et al. (2008) identified homozygosity for a 1024G-T transversion that resulted in a val342-to-leu amino acid substitution (V342L) in the ligand-binding domain.
Ansar, M., Amin Ud Din, M., Arshad, M., Sohail, M., Faiyaz-Ul-Haque, M., Haque, S., Ahmad, W., Leal, S. M. A novel autosomal recessive non-syndromic deafness locus (DFNB35) maps to 14q24.1-14q24.3 in large consanguineous kindred from Pakistan. Europ. J. Hum. Genet. 11: 77-80, 2003. [PubMed: 12529709] [Full Text: https://doi.org/10.1038/sj.ejhg.5200905]
Collin, R. W. J., Kalay, E., Tariq, M., Peters, T., van der Zwaag, B., Venselaar, H., Oostrik, J., Lee, K., Ahmed, Z. M., Caylan, R., Li, Y., Spierenburg, H. A., and 17 others. Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. Am. J. Hum. Genet. 82: 125-138, 2008. [PubMed: 18179891] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.008]
Doege, C. A., Inoue, K., Yamashita, T., Rhee, D. B., Travis, S., Fujita, R., Guarnieri, P., Bhagat, G., Vanti, W. B., Shih, A., Levine, R. L., Nik, S., Chen, E. I., Abeliovich, A. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488: 652-655, 2012. [PubMed: 22902501] [Full Text: https://doi.org/10.1038/nature11333]
Giguere, V., Yang, N., Segui, P., Evans, R. M. Identification of a new class of steroid hormone receptors. Nature 331: 91-94, 1988. [PubMed: 3267207] [Full Text: https://doi.org/10.1038/331091a0]
Luo, J., Sladek, R., Bader, J. A., Matthyssen, A., Rossant, J., Giguere, V. Placental abnormalities in mouse embryos lacking orphan nuclear receptor ERR-beta. Nature 388: 778-782, 1997. [PubMed: 9285590] [Full Text: https://doi.org/10.1038/42022]
Sladek, R., Beatty, B., Squire, J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Giguere, V. Chromosomal mapping of the human and murine orphan receptors ERR-alpha (ESRRA) and ERR-beta (ESRRB) and identification of a novel human ERR-alpha-related pseudogene. Genomics 45: 320-326, 1997. [PubMed: 9344655] [Full Text: https://doi.org/10.1006/geno.1997.4939]