CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.

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.

Effects of hormonal replacement therapy on the postural balance among postmenopausal women.

OBJECTIVE: To establish whether hormone replacement therapy affects postural balance in postmenopausal women. METHODS: Nineteen healthy postmenopausal women with vasomotor symptoms were included. Median age was 54 years, median time since menopause was 3 years. They underwent dynamic posturography before and after 4 and 12 weeks of transdermal estrogen treatment (17 beta-estradiol 50 micrograms/day) as well as after 2 additional weeks of combined estrogen-progestagen treatment. The dynamic posturography method quantifies the amplitude, frequency, and pattern of body sway and tests the visual, vestibular, and somatosensory systems, which together maintain balance. The two most difficult tests either cancel visual and distort somatosensory inputs or give distorted information from both the visual and somatosensory systems. RESULTS: Hormone replacement therapy increased static balance performance assessed by dynamic posturography. A highly significant improvement was seen in the two most difficult tests between the pretreatment test and the test performed after 4 weeks of estrogen therapy (P < .01, P < .001, respectively). This improvement was sustained after 12 weeks and also during the 14th week, with the women on combined estrogen-progestagen treatment. CONCLUSION: Estrogen treatment increased balance performance measured by dynamic posturography, indicating that the beneficial effects from estrogens on postmenopausal fracture risk may include central nervous system effects on balance. Two weeks' addition of gestagen to the treatment regimen did not counteract the estrogen effects.

Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium.

The Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.

Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11.

Usher syndrome is the most commonly recognized cause of combined visual and hearing loss in technologically developed countries. There are several different types and all are inherited in an autosomal recessive manner. There may be as many as five different genes responsible for at least two closely related phenotypes. The nature of the gene defects is unknown, and positional cloning strategies are being employed to identify the genes. This is a report of the localization of one gene for Usher syndrome type I to chromosome 11q, probably distal to marker D11S527. Another USH1 gene had been previously localized to chromosome 14q, and this second localization establishes the existence of a new and independent locus for Usher syndrome.

Usher syndrome: clinical findings and gene localization studies.

The issue of genetic heterogeneity is a critical problem in the localization of the gene(s) for Usher syndrome. Based on the data obtained on families studied to date, the differences between type I and type II Usher syndrome appear quite distinct with regard to auditory and vestibular function. Although the majority of families can be confidently diagnosed as typical type I or type II, clinical investigations revealed four families with findings that did not fit into either of the two more common subtypes. These findings emphasize the critical importance of an in-depth clinical analysis concomitant with the linkage investigation to assure accurate subtyping of Usher syndrome. Based on an analysis of only those families with definite type I or type II Usher syndrome, approximately 17% of the genome can be excluded as a potential site of the gene for type I, and 14% can be excluded as the site for the type II gene. This study will continue until the Usher gene(s) is successfully localized.

Usher syndrome: an otoneurologic study.

Usher syndrome is an autosomal recessive disorder characterized by severe hearing loss or deafness and retinitis pigmentosa. Eleven families with 25 affected members were studied. The test battery included genetic studies, clinical examination, audiological, ophthalmologic, and otoneurological tests, and magnetic resonance imaging. Sixteen affected persons had profound hearing loss or were considered anacusic, with absent bilateral vestibular responses. These patients had varying degrees of retinitis pigmentosa. These 16 patients were considered to have type I Usher syndrome. Nine persons were diagnosed as Usher type II with a moderate to profound hearing loss, normal vestibular function, and retinitis pigmentosa of varying degree. Magnetic resonance imaging was normal in all cases. Otoneurological tests indicated no central nervous system disturbances. The conclusion is that hearing loss and balance problems in Usher syndrome are due to inner ear damage with no evidence of central nervous system disturbances. Furthermore, the ataxia seen in Usher type I is due to a combination of retinitis pigmentosa and bilateral peripheral vestibular deficiency.