Usher Syndrome, Type Iiia

A number sign (#) is used with this entry because Usher syndrome type IIIA (USH3A) is caused by homozygous or compound heterozygous mutation in the CLRN1 gene (606397) on chromosome 3q25.

Mutation in the same gene can cause a form of nonsyndromic retinitis pigmentosa (RP61; 614180).

Description

Usher syndrome type III is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life (Karjalainen et al., 1985; Pakarinen et al., 1995).

For a discussion of phenotypic heterogeneity of Usher syndrome, see USH1 (276900).

Genetic Heterogeneity of Usher syndrome Type III

Usher syndrome type IIIB (614504) is caused by mutation in the HARS gene (142810) on chromosome 5q31.3.

Clinical Features

Karjalainen et al. (1985) described this distinct type of Usher syndrome as being characterized by progressive hearing loss and vestibular hypoactivity. Smith et al. (1992) described a family in the French Acadian population of southwestern Louisiana in which 2 males had a clinical phenotype like that in the family reported by Karjalainen et al. (1985). Both Usher syndrome type I (276900) and Usher syndrome type II (276901) are frequent among the Louisiana Acadians but this family appeared to have a separate form.

Shinkawa and Nadol (1986) studied the inner ear of a patient with type III Usher syndrome who died at age 52 of metastatic cancer. They found hair cell loss in the basal turn, severe loss of spiral ganglion cells, widespread neural degeneration in the cochlea, and discrete collections of degenerating supporting cells in the organ of Corti. The pattern of neural degeneration bore some similarity to abnormalities in the retina in retinitis pigmentosa.

Aller et al. (2004) did not consider progressive hearing loss to be the definitive parameter in distinguishing Usher syndrome type III from Usher syndrome types I and II. They noted that 3 patients reported by Adato et al. (2002) with a mutation in the CLRN1 gene (606397.0006) had profound stable deafness and vestibular hyporeflexia.

Malm et al. (2011) evaluated visual function, comprising both the severity of the rod cone degeneration and the function in the macular region, in 12 patients genotyped as Usher syndrome 1B, 1D, 1F, 2A, 2C, or 3A, including 3 families with affected sibs, and confirmed phenotypic heterogeneity between sibs with the same genotype and between patients with different genotypes. In all patients examined with ERG, the 30 Hz flicker response revealed remaining cone function. Optical coherence tomography (OCT) demonstrated loss of foveal depression with distortion of the foveal architecture in the macula of all patients. The foveal thickness ranged from 159 to 384 micrometers and was not correlated with retinal function.

Population Genetics

Usher syndrome type III has been estimated to comprise 2% of all Usher syndrome cases; however, based on clinical criteria, 42% of patients with Usher syndrome in Finland are thought to have USH3, suggesting gene enrichment by a founder effect (Sankila et al. (1994, 1995)). Joensuu et al. (2001) identified the Finnish founder mutation (606397.0001).

Mapping

In Finnish families segregating Usher syndrome type III, Sankila et al. (1994, 1995) excluded previous chromosomal sites at which Usher syndrome had been mapped. Using highly polymorphic microsatellite markers for a systematic search for the USH3 locus by genetic linkage analyses of 11 multiply affected families, they assigned the disease locus to 3q21-q25. Of 20 parental disease chromosomes, 15 had identical alleles at 3 marker loci covering a 3-cM genetic distance, including the putative USH3 locus. They stated that this was the fifth distinctive form of Usher syndrome to be identified.

Joensuu et al. (1996) typed a total of 32 pedigrees from a geographically isolated Finnish founder population for polymorphisms in the USH3 region of chromosome 3. By analysis of linkage disequilibrium and historical recombinations in 77 USH3 chromosomes, the location of the Finnish USH3 mutation was narrowed to an interval of approximately 1 cM between markers D3S1299 and D3S3625. The profilin-2 gene (PFN2; 176590) was mapped to the vicinity but was excluded as a candidate for USH3 by sequencing.

Gasparini et al. (1998) reported linkage analysis of an Italian family with Usher syndrome type III and confirmed linkage at 3q24-q25 with a maximum lod score obtained with marker D3S1299 (maximum lod = 2.43 at theta = 0.00).

Molecular Genetics

In the 2 Finnish families reported by Sankila et al. (1995) and Joensuu et al. (1996) and the Italian family reported by Gasparini et al. (1998) with Usher syndrome type III, Joensuu et al. (2001) identified mutations in the CLRN1 gene (606397.0001-606397.0003).

Adato et al. (1999) studied a nonconsanguineous Jewish Yemenite family with 2 affected and 6 healthy sibs, originally reported by Adato et al. (1997), in which the 2 affected brothers had different Usher syndrome phenotypes: one had typical USH3 phenotype, whereas the other had typical USH1 (276900) phenotype. Adato et al. (1999) found a double mutation of the MYO7A gene (276903), which is responsible for USH1B, on 1 maternal chromosome in the brother with the more severe USH1 phenotype; the mother and 2 unaffected sibs also carried the double mutation. The authors suggested a possible synergistic interaction between MYO7A and the USH3 gene product that might increase the severity of the deafness as part of the clinical symptoms associated with USH3. In the course of their study of this family, Adato et al. (1999) narrowed the assignment of the USH3 gene to the interval between D3S1299 and D3S3625. Adato et al. (2002) restudied this family and identified homozygosity for a 23-bp deletion of the CLRN1 gene (606397.0007) in the 2 affected brothers with different Usher syndrome phenotypes. Adato et al. (2002) noted that the mother and 2 sibs who carried only the double mutation in MYO7A were healthy, whereas in the context of a homozygous CLRN1-null mutation, the presence of 1 null mutation in the MYO7A gene mimicked haploinsufficiency, illustrating a departure from the monogenic model for Usher syndrome.

Fields et al. (2002) described 4 novel disease-causing mutations in the CLRN1 gene, including one that appeared to be relatively common in the Ashkenazi Jewish population (N48K; 606397.0004). Adato et al. (2002) detected the N48K missense mutation in 6 affected individuals from 4 unrelated families of Eastern European Jewish origin; shared microsatellite and SNP haplotypes on carrier chromosomes suggested the existence of a founder effect for this mutation.

In a cohort of 40 Ashkenazi Jewish patients with Usher syndrome, Ness et al. (2003) found that the 16 (40%) who were clinically classified as having Usher syndrome type III were homozygous for the N48K mutation. The carrier frequency of N48K was 0.7% (95% CI, 0.0-1.6%) among Ashkenazi Jews in the New York area, with a predicted Usher syndrome type III prevalence of 1.2 per 100,000. Despite the genetic homogeneity of Usher syndrome type III in this group, there was a wide range of phenotypic severity displayed by the N48K homozygotes. Age at onset of the auditory phenotype varied from infancy to more than 35 years. A 56-year-old woman had onset of the ocular phenotype in early childhood ending with no useful vision, whereas hearing loss began after age 35 years, progressing to moderate to severe.

Aller et al. (2004) screened for mutations in the CLRN1 gene in Spanish patients with Usher syndrome and found mutations in only 2 families. They identified 1 patient with Usher syndrome type III who was homozygous for a C40G mutation (606397.0008). They noted that only 1 other mutation had been reported in the USH3A gene in Spanish families with Usher syndrome (606397.0006). These 2 families accounted for only 1.7% of Spanish families with Usher syndrome.

Animal Model

Geng et al. (2009) developed a Clrn1 -/- mouse model for Usher syndrome type III. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells than inner hair cells. Clrn1 -/- mice showed early-onset hearing loss that rapidly progressed to severe levels. Two to 3 weeks after birth (postnatal day 14 to 21), Clrn1-null mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By postnatal day 21, approximately 70% of Clrn1-null mice had no detectable ABR, and by postnatal day 30, these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1 -/- mice. Vestibular function in Clrn1-null mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of outer hair cell stereocilia was seen as early as postnatal day 2 and by postnatal day 21 outer hair cell loss was observed. Geng et al. (2009) concluded that CLRN1 is necessary for hair cell function and associated neural activation.