Deafness, Autosomal Recessive 18a

A number sign (#) is used with this entry because of evidence that nonsyndromic autosomal recessive deafness-18A (DFNB18A) is caused by homozygous mutation in the gene encoding harmonin (605242) on chromosome 11p15. Mutations in the harmonin gene also cause Usher syndrome type IC (USH1C; 276904).

A form of autosomal recessive deafness designated DFNB18B (614945), which also maps to chromosome 11p15, is caused by mutation in the OTOG gene (604487).

Clinical Features

Jain et al. (1997, 1998) reported a large consanguineous Indian family in which several members had profound, prelingual, nonsyndromic sensorineural deafness. Vestibular function and visual function were normal.

Mapping

Jain et al. (1997, 1998) studied the linkage of autosomal recessive nonsyndromic sensorineural hearing loss segregating in a large consanguineous Indian family and found that it maps to 11p15.1-p14. They designated the new locus DFNB18. Maximum lod scores of 4.30 and 3.93 at theta = 0.0 were obtained for the polymorphic microsatellite markers D11S1888 and D11S4130. Haplotype analysis localized the gene between D11S1307 and D11S1308, spanning a distance of approximately 4 cM and encompassing the USH1C region. Based on the linkage data, Jain et al. (1997, 1998) postulated that DFNB18 and USH1C are allelic. (Usher syndrome, of which there are many forms, has retinopathy in association with deafness.) A precedent has been set by the demonstration that different mutations in the gene encoding myosin-7A (276903) can cause either USH1B or DFNB2 (600060). The MYO7A gene is located on the long arm of chromosome 11.

Molecular Genetics

Verpy et al. (2000) identified a PDZ-domain-containing gene on 11p15.1-p14, mutations in which are responsible for USH1C. They proposed that the USH1C gene underlies the DFNB18 form of isolated deafness also. They suggested that the fact that several of the inner ear Ush1c transcripts of the mouse are not present in the eye is consistent with mutations in the USH1C gene underlying a form of isolated deafness. Mutations in connexin-26 (121011) provide another example of syndrome deafness and nonsyndromic deafness being caused by different alleles of the same gene: isolated autosomal recessive deafness (220290), autosomal dominant isolated deafness (601544), and keratoderma with deafness (148350).

In the family in which Jain et al. (1998) mapped DFNB18 to 11p, Ahmed et al. (2002) identified a leaky splice site mutation in the harmonin gene (605242.0008), indicating that Usher syndrome type IC and DFNB18 are allelic.

Ouyang et al. (2002) indeed demonstrated that mutations in alternatively spliced exons of USH1C cause nonsyndromic recessive deafness DFNB18. They screened 32 Chinese multiplex families with nonsyndromic recessive deafness for USH1C mutations. In 1 family, congenital profound deafness without RP was associated with a C-to-G transversion in the alternatively spliced exon D, predicting an arg608-to-pro (605242.0009) amino acid substitution in the proline-, serine-, and threonine-rich region of harmonin. They also screened 320 deaf probands from other ethnic backgrounds and found 3 who were heterozygous for changes in the alternately spliced exons. None of these mutations were detected in DNA from 200 control subjects with normal hearing, including 110 Chinese. These findings showed that USH1C mutations can also cause nonsyndromic deafness and that some harmonin isoforms are specifically required for inner ear function.

Animal Model

Johnson et al. (2003) mapped 2 recessive, allelic murine mutations causing circling behavior and deafness to the same region on chromosome 7. The 'deaf circler' (dfcr) mutation is a 12.8-kb intragenic deletion in Ush1c that eliminates 3 constitutive and 5 alternatively spliced exons. The 'deaf circler-2 Jackson' (dfcr-2J) mutation is a 1-bp deletion in an alternatively spliced exon of Ush1c that creates a transcriptional frameshift, changing 38 amino acid codons before introducing a premature stop codon. Both mutations cause congenital deafness and severe balance deficits due to inner ear dysfunction. The stereocilia of cochlear hair cells are disorganized and splayed in mutant mice, with subsequent degeneration of the hair cells and spiral ganglion cells. Harmonin has been shown to bind, by means of its PDZ-domains, with the products of other Usher syndrome genes, including Myo7a, Cdh23 (605516), and Sans (USH1G; 607696). The complexes formed by these protein interactions are thought to be essential for maintaining the integrity of hair cell stereocilia.