Deafness, Autosomal Recessive 48
A number sign (#) is used with this entry because autosomal recessive deafness-48 (DFNB48) is caused by homozygous mutation in the CIB2 gene (605564) on chromosome 15q25.
DescriptionDFNB48 is an autosomal recessive form of deafness. Affected individuals have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies (summary by Riazuddin et al., 2012).
MappingBy linkage analysis in 5 large consanguineous Pakistani families with nonsyndromic deafness segregating as an autosomal recessive trait, Ahmad et al. (2005) mapped the phenotype locus to chromosome 15q23-q25.1. Analysis in 1 of the families demonstrated linkage of the deafness locus, designated DFNB48, to D15S1005 (lod score of 8.6 at theta = 0), and a critical linkage interval of approximately 7 cM was defined between D15S216 and D15S1041. Affected individuals had bilateral profound congenital hearing loss.
Ahmed et al. (2009) sequenced the TLE3 gene within the DFNB48 locus but did not identify any pathogenic alleles.
Molecular GeneticsIn affected members of 54 Pakistani families with autosomal recessive deafness-48, Riazuddin et al. (2012) identified a homozygous mutation in the CIB2 gene (F91S; 605564.0001). Haplotype analysis indicated a founder effect. Two additional homozygous CIB2 mutations were found in other families with DFNB48 (C99W, 605564.0002 and I123T, 605564.0003). Transfection of the F91S and C99W mutations in COS-7 cells decreased or abolished the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype, whereas transfection of the I123T mutation increased the ability of CIB2 to decrease calcium release compared to wildtype. These findings suggested that the mutations had an effect on CIB2 calcium-binding or buffering activity, and indicated that loss of this gene results in defects in calcium regulation.
Population GeneticsRiazuddin et al. (2012) estimated that CIB2 mutations may account for up to 7.25% of Pakistani families with autosomal recessive deafness.