A Novel ESRRB Deletion Is a Rare Cause of Autosomal Recessive Nonsyndromic Hearing Impairment among Pakistani Families

Kwanghyuk Lee,Muhammad Ansar,Suzanne M Leal,Regie Lyn P Santos-Cortez,Wasim Ahmad,Saadullah Khan

doi:10.4061/2011/368915

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.

Highlights

Hearing impairment (HI) has been associated with estrogen physiology for decades
Autosomal recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB35 was shown to be due to mutations in the estrogen-related receptor beta or ESRRB gene (MIM 602167; 2)
We report a novel deletion mutation of glutamic acid residue in ligand-binding domain (LBD) domain of ESRRB gene which is responsible for autosomal recessive nonsyndromic hearing impairment (ARNSHI)

Summary

Introduction

Hearing impairment (HI) has been associated with estrogen physiology for decades. Autosomal recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB35 was shown to be due to mutations in the estrogen-related receptor beta or ESRRB gene (MIM 602167; 2). ESRRB belongs to a subfamily of orphan nuclear receptors that are structurally related to estrogen receptors (ER) but do not directly bind estrogen. The ESRR proteins have DNA-binding and ligand-binding domains, which are both required for transcriptional regulation of ER target genes. The ligand-binding domain (LBD) provides structural stability and influences the binding affinity of the ESRRB protein [2].

Material and Methods

Results and Discussion

Conclusion