Deafness, Autosomal Recessive 28

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-28 (DFNB28) is caused by homozygous mutation in the TRIOBP gene (609761) on chromosome 22q13.

Mapping

Shahin et al. (2006) ascertained children with prelingual hearing loss from Palestinian schools for the deaf and identified an Orthodox Christian family with autosomal recessive bilateral symmetrical profound sensorineural hearing loss. Genomewide linkage analysis yielded a maximum lod score of 4.19 at marker D22S423 on chromosome 22q13.1. Fine mapping defined a 6.3-Mb region bounded by D22S1045 and D22S282, designated DFNB28 by them.

Riazuddin et al. (2006) performed genomewide linkage analysis in a Pakistani family whose deafness was not linked to genetic markers at known nonsyndromic recessive deafness loci. A 2-point lod score of 3.1 was achieved with marker D22S272 on chromosome 22q13.

Molecular Genetics

In 4 Palestinian Orthodox Christian families with hearing loss linked to the DFNB28 region, Shahin et al. (2006) found a nonsense mutation in the TRIOBP gene, arg347 to ter (R347X; 609761.0001), in homozygosity in all affected individuals. Three other Palestinian Muslim families whose deafness mapped to the DFNB28 region carried another termination mutation in TRIOBP (Q581X; 609761.0002). One family was found in which 2 deaf children were compound heterozygous for R347X and Q581X. They also found a novel missense mutation in compound heterozygosity with the R347X mutation in a child with profound hearing loss.

Riazuddin et al. (2006) sequenced all exons of the TRIOBP gene in genomic DNA of affected persons from each of the 12 Pakistani and Indian families identified by them. They identified 6 mutations, including 4 nonsense and 2 frameshift, in 7 families. All these mutations were located in exon 6 of the TRIOBP gene, and all 6 alleles resulted in truncation of the protein. In 5 families no mutation in TRIOBP was found, indicating the presence of additional exons of the TRIOBP gene, undetected mutations, or locus heterogeneity.

Animal Model

Kitajiri et al. (2010) noted that the Triobp1 isoform has ubiquitous expression, whereas Triobp4 and Triobp5 isoforms have expression predominantly in the eye and inner ear. The authors generated a Triobp4/5-deficient mouse recapitulating human DFNB28 deafness. Triobp1-null mice were embryonic lethal, suggesting an essential role in development for this isoform. In Triobp4/5-null mice, rootlets in inner ear hair cells failed to develop, resulting in normal-length stereocilia that were abnormally flexible at the pivot points and were easily damaged by overstimulation. Although mutant hair cells were still able to function in mechanoelectrical transduction prior to the onset of hearing, they were unlikely to have normal mechanosensitivity in vivo due to both decreased pivotal stiffness and increased fragility. The findings indicated that dense bundling of actin filaments by TRIOBP is essential for the biogenesis of rootlets that provide durable flexibility at the taper, and mechanical rigidity to the stereocilia bundle.