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

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.

Figure 1

Pedigree drawing of family 4243. Filled symbols represent individuals with ARNSHI, and clear symbols represent hearing individuals. Displayed under each individual are the SNP markers within the region of the ESRRB gene and the p.Glu340del mutation. The haplotype segregating with the ARNSHI phenotype is shown within a box. The homozygous region that is found only in ARNSHI individuals is bounded by rs917284 (chr14 : 71.8 Mb) and rs2043585 (chr14 : 79.0 Mb). The black arrow indicates the position of ESRRB gene amid the SNP marker loci.

Figure 2

Audiogram of individual IV-4 demonstrates bilateral severe-to-profound HI at all frequencies. Air conduction threshold testing was performed for the right (circles) and left (crosses) ears.