Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I.

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

Histopathologic features of the temporal bone in usher syndrome type I.

Temporal bones of 2 patients with Usher syndrome type I were examined using light microscopy. In both patients, findings from histopathologic examination of the cochlea were characterized by degeneration of the organ of Corti, which was most marked in the basal turn, atrophy of the stria vascularis, and a decrease in the number of spiral ganglion cells. The cochlear nerve appeared to be diminished. The sensory epithelium of the saccular and utricular maculae of patient 1 was normal for age. The left temporal bone of patient 2, classified as Usher syndrome genetic subtype USH1D or USH1F, demonstrated the typical signs of severe cochleosaccular degeneration. Present cases and cases from the literature were reviewed in search of an explanation for the above-described differences in histologic findings.

Genetic heterogeneity of Usher syndrome.

Progress towards the understanding of the molecular basis of US has been substantial. Nine different loci have been found to be responsible and two have had the specific gene identified. This information is expected to lay the foundation for the eventual development of new treatment strategies. Usher syndrome is the combined loss of both of humans most important two senses and a better understanding of the genes involved should not only help the families with US but will also provide much needed basic information about the hearing and visual systems.

Genetic heterogeneity of Usher syndrome type II: localisation to chromosome 5q.

Usher syndrome is a group of autosomal recessive disorders that includes retinitis pigmentosa (RP) with hearing loss. Usher syndrome type II is defined as moderate to severe hearing loss with RP. The USH2A gene at 1q41 has been isolated and characterised. In 1993, a large Usher II family affected with a mild form of RP was found to be unlinked to 1q41 markers. Subsequent linkage studies of families in our Usher series identified several type II families unlinked to USH2A and USH3 on 3q25. After a second unlinked family with many affected members and a mild retinal phenotype was discovered, a genome search using these two large families showed another Usher II locus on 5q (two point lod = 3.1 at D5S484). To date, we have identified nine unrelated 5q linked families (maximum combined multipoint lod = 5.86) as well as three Usher II families that show no significant linkage to any known Usher loci. Haplotype analysis of 5q markers indicates that the new locus is flanked by D5S428 and D5S433. Review of ophthalmological data suggests that RP symptoms are milder in 5q linked families; the RP is often not diagnosed until patients near their third decade. Enamel hypoplasia and severe, very early onset RP were observed in two of the three unlinked families; dental anomalies have not been previously described as a feature of Usher type II.

Semen analysis in the Usher syndrome type 2A.

Semen analysis in patients with Usher syndrome suggested that defective connecting cilia axonemes may be involved in the irreversible, progressive loss of photoreceptors in Usher's syndrome. In the framework of clinical genetic research into Usher syndrome, a pilot study was set up to test these findings. The semen of 6 Usher 2A patients was analysed. The fertility status of the study group of Usher 2A patients was evaluated, including semen analysis, supplemented by electron microscopic examination of the spermatozoa. Except for a significantly increased pH value, no abnormalities were found in the functional semen analysis, whereas electron microscopy revealed microtubular tail abnormalities. The latter finding was of little relevance, however, in view of the normal motility of the spermatozoa observed in these patients. There were no fertility problems in our group of Usher 2A patients, nor have any been mentioned in Usher patients in general. Earlier study findings were not supported by our data.

Hearing impairment related to age in Usher syndrome types 1B and 2A.

OBJECTIVE: To evaluate hearing impairment in 2 common genetic subtypes of Usher syndrome, USH1B and USH2A. DESIGN: Cross-sectional analysis of hearing threshold related to age in patients with genotypes determined by linkage and mutation analysis. SETTING: Otolaryngology department, university referral center. PATIENTS: Nineteen patients with USH1B and 27 with USH2A were examined. All participants were living in the Netherlands and Belgium. MAIN OUTCOME MEASURE: Pure tone audiometry of the best ear at last visit. RESULTS: The patients with USH1B had residual hearing without age dependence, with minimum thresholds of 80, 95, and 120 dB at 0.25, 0.5, and 1 to 2 kHz, respectively. Mean thresholds of patients with USH2A were about 45 to 55 dB better than these minimum values. Distinctive audiographic features of patients with USH2A were maximum hearing thresholds of 70, 80, and 100 dB at 0.25, 0.5, and 1 kHz, respectively, only at younger than 40 years. Progression of hearing impairment in USH2A was 0.7 dB/y on average for 0.25 to 4 kHz and could not be explained by presbyacusis alone. CONCLUSIONS: The USH1B and USH2A can be easily distinguished by hearing impairment at younger than 40 years at the low frequencies. Hearing impairment in our patients with USH2A could be characterized as progressive.

Hearing loss in the RBF/DnJ mouse, a proposed animal model of Usher syndrome type IIa.

The Usher syndromes (US) are a group of inherited disorders that feature autosomal recessive neurosensory hearing loss or deafness with retinitis pigmentosa (RP). Moderate to severe non-progressive high frequency hearing loss with RP and normal vestibular function describes Usher syndrome type IIa, which has been localized to 1q41. Severe retinal degeneration in the inbred mouse strain RBF/DnJ is caused by rd3, a recessive gene located on mouse chromosome 1 distal to akp1 in a region which is orthologous to human 1q32-q42. We evaluated rd3 as a candidate for orthology with USH2A by first reducing and refining the relatively broad region in which rd3 is thought to reside. DNA of offspring from an RBF/DnJ x MOLF/Ei backcross was genotyped with PCR markers closely flanking the predicted location of rd3. Our haplotype analysis re-positioned rd3 to a 3.6 cM region between markers D1Mit273 (cen) and D1Mit209 (tel), consistent with the expected position of an USH2A murine orthologue. Consequently, rd3 is a positional candidate for Usher type IIa. Next we assessed the rd3/rd3 audiological phenotype to see how closely it paralleled that of Usher IIa. Audiological evaluation of mice at various ages revealed evidence of high frequency progressive hearing loss, previously unreported in the RBF/DnJ strain. However, this newly discovered hearing deficit was observed to be inherited independently of rd3, establishing that a completely different gene is responsible.

Human bZIP transcription factor gene NRL: structure, genomic sequence, and fine linkage mapping at 14q11.2 and negative mutation analysis in patients with retinal degeneration.

The NRL gene encodes an evolutionarily conserved basic motif-leucine zipper transcription factor that is implicated in regulating the expression of the photoreceptor-specific gene rhodopsin. NRL is expressed in postmitotic neuronal cells and in lens during embryonic development, but exhibits a retina-specific pattern of expression in the adult. To understand regulation of NRL expression and to investigate its possible involvement in retinopathies, we have determined the complete sequence of the human NRL gene, identified a polymorphic (CA)n repeat (identical to D14S64) within the NRL-containing cosmid, and refined its location by linkage analysis. Since a locus for autosomal recessive retinitis pigmentosa (arRP) has been linked to markers at 14q11 and since mutations in rhodopsin can lead to RP, we sequenced genomic PCR products of the NRL gene and of the rhodopsin-Nrl response element from a panel of patients representing independent families with inherited retinal degeneration. The analysis did not reveal any causative mutations in this group of patients. These investigations provide the basis for delineating the DNA sequence elements that regulate NRL expression in distinct neuronal cell types and should assist in the analysis of NRL as a candidate gene for inherited diseases/syndromes affecting visual function.

Genetic heterogeneity of Usher syndrome type II in a Dutch population.

The Usher syndromes are a group of autosomal recessive disorders characterised by retinitis pigmentosa (RP) with congenital, stable (non-progressive) sensorineural hearing loss. Profound deafness, RP, and no vestibular responses are features of Usher type I, whereas moderate to severe hearing loss and RP with normal vestibular function describe Usher type II. The gene responsible for most cases of Usher II, USH2a, is on chromosome 1q41; at least one other Usher II gene (as yet unlinked) is known to exist. Usher III presents with a progressive hearing loss that can mimic the audiometric profile seen in Usher II. A gene causing Usher III in a group of Finnish families, USH3, resides on chromosome 3q. Since the phenotypes for Usher II and III overlap, it is important to determine how frequently Usher IIa, Usher IIb, and Usher III occur in a clinical population of non-Usher I patients. DNA was collected from 29 Dutch families and genotyped with six DNA markers known to flank the USH2a gene closely, and with five markers that flank USH3. Results of haplotype and linkage analysis were consistent with linkage to the USH2a locus in 26 of these 29 Dutch families. Three families displayed no linkage to 1q41 markers, and one of these three families appeared unlinked to 3q markers as well; current haplotypes of the other two families are inconclusive for linkage with the USH3 locus without further genotyping. While an A test for heterogeneity of USH2a was statistically significant, no convincing evidence of linkage to USH3 was found in this Dutch sample. Consequently, the frequency of the unlinked variety of Usher IIa (Usher IIb) in The Netherlands was estimated as 0.104. To determine if marker alleles could be used to differentiate Usher type IIa from Usher IIb, parental chromosomes of the 26 Usher IIa families were analysed for significant non-random association of specific alleles from flanking loci with USH2a, but no linkage disequilibrium was observed in this Dutch population.

Genetic heterogeneity of Usher syndrome type II.

Usher syndrome is an autosomal recessive disorder characterised by retinitis pigmentosa and congenital sensorineural hearing loss. A gene for Usher syndrome type II (USH2) has been localised to chromosome 1q32-q41. DNA from a family with four of seven sibs affected with clinical characteristics of Usher syndrome type II was genotyped using markers spanning the 1q32-1q41 region. These included D1S70 and D1S81, which are believed to flank USH2. Genotypic results and subsequent linkage analysis indicated non-linkage of this family to these markers. The A test analysis for heterogeneity with this family and 32 other Usher type II families was statistically significant at p < 0.05. Further clinical evaluation of this family was done in light of the linkage results to determine if any phenotypic characteristics would allow for clinical identification of the unlinked type. No clear phenotypic differences were observed; however, this unlinked family may represent a previously unreported subtype of Usher type II characterised by a milder form of retinitis pigmentosa and mild vestibular abnormalities. Heterogeneity of Usher syndrome type II complicates efforts to isolate and clone Usher syndrome genes using linkage analysis and limits the use of DNA markers in early detection of Usher type II.

Exclusion of autosomal dominant polycystic kidney disease type II (ADPKD2) from 160 cM of chromosome 1.

Autosomal dominant polycystic kidney disease is a heritable disorder and recent studies have shown genetic heterogeneity, with some, but not all, families showing linkage with markers on chromosome 16p. Members of a large ADPKD family, unlinked to chromosome 16, have been typed for 12 marker loci located on both arms of chromosome 1. Multipoint analysis excluded ADPKD2 from the region between D1S81 (pTHH33) and D1S67 (pHHH106) on the long arm and between Rh and PGM1 on the short arm. This excludes the disease locus from about 61% of chromosome 1.