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William J. Kimberling - One of the best experts on this subject based on the ideXlab platform.
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Evidence of genetic heterogeneity in Alberta Hutterites with Usher Syndrome type I
Molecular Vision, 2012Co-Authors: Qi Zhou, Richard J.h. Smith, William J. Kimberling, Chaeli Lenger, M. Ye, Ordan J. Lehmann, Ian R. MacdonaldAbstract:PURPOSE: To identify the genetic defect in a Hutterite population from northern Alberta with Usher Syndrome type I. METHODS: Complete ophthalmic examinations were conducted on two boys and two girls from two related Hutterite families diagnosed with Usher Syndrome type I. DNA from patients and their parents was first evaluated for a mutation in exon 10 of the protocadherin-related 15 (PCDH15) gene (c.1471delG), previously reported in southern Alberta Hutterite patients with Usher Syndrome (USH1F). Single nucleotide polymorphic linkage analysis was then used to confirm another locus, and DNA was analyzed with the Usher Chip v4.0 platform. RESULTS: Severe hearing impairment, unintelligible speech, and retinitis pigmentosa with varying degrees of visual acuity and visual field loss established a clinical diagnosis of Usher Syndrome type I. The patients did not carry the exon 10 mutation in the PCDH15 gene; however, with microarray analysis, a previously reported mutation (c.52C>T; p.Q18X) in the myosin VIIA (MYO7A) gene was found in the homozygous state in the affected siblings. CONCLUSIONS: The finding of a MYO7A mutation in two related Hutterite families from northern Alberta provides evidence of genetic heterogeneity in Hutterites affected by Usher Syndrome type I.
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frequency of Usher Syndrome in two pediatric populations implications for genetic screening of deaf and hard of hearing children
Genetics in Medicine, 2010Co-Authors: William J. Kimberling, Edward S. Cohn, Michael S Hildebrand, Eliot A Shearer, Maren Jensen, Jennifer A Halder, Karmen M Trzupek, Richard G Weleber, Edwin M StoneAbstract:Purpose: Usher Syndrome is a major cause of genetic deafness and blindness. The hearing loss is usually congenital and the retinitis pigmentosa is progressive and first noticed in early childhood to the middle teenage years. Its frequency may be underestimated. Newly developed molecular technologies can detect the underlying gene mutation of this disorder early in life providing estimation of its prevalence in at risk pediatric populations and laying a foundation for its incorporation as an adjunct to newborn hearing screening programs. Methods: A total of 133 children from two deaf and hard of hearing pediatric populations were genotyped first for GJB2/6 and, if negative, then for Usher Syndrome. Children were scored as positive if the test revealed ≥1 pathogenic mutations in any Usher gene. Results: Fifteen children carried pathogenic mutations in one of the Usher genes; the number of deaf and hard of hearing children carrying Usher Syndrome mutations was 15/133 (11.3%). The population prevalence was estimated to be 1/6000. Conclusion: Usher Syndrome is more prevalent than has been reported before the genome project era. Early diagnosis of Usher Syndrome has important positive implications for childhood safety, educational planning, genetic counseling, and treatment. The results demonstrate that DNA testing for Usher Syndrome is feasible and may be a useful addition to newborn hearing screening programs.
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The prevalence of Usher Syndrome in Sweden: a nationwide epidemiological and clinical survey
Audiological Medicine, 2009Co-Authors: Mehdi Sadeghi, William J. Kimberling, Lisbeth Tranebjœrg, Claes MöllerAbstract:The purpose of this study was to estimate the prevalence of Usher Syndrome types I, II and III in Sweden and to estimate possible regional differences in the prevalence of different Usher Syndrome subtypes within the country. Probands were ascertained through multiple sources and almost complete ascertainment was achieved. A total of 370 subjects with a referring diagnosis of Usher was ascertained. Of those, 77 subjects proved to have an incorrect preliminary diagnosis. Of the remaining 293 individuals, 140 were found to have Usher Syndrome type I, 122 subjects were diagnosed as type II, and 27 subjects had Usher Syndrome type III. The corresponding prevalence in Sweden was estimated to be 1.6/100,000 for type I, 1.4/100.000 for type II and 0.3/100.000 for type III. The prevalence of Usher I was found to be significantly higher (8.6/100.000) in the two northernmost counties. This is consistent with an earlier report made in the 1950s. Similar geographic concentrations of Usher II and III were not observed...
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Audiological findings in Usher Syndrome types IIa and II (non-IIa)
International Journal of Audiology, 2009Co-Authors: Mehdi Sadeghi, William J. Kimberling, Edward S. Cohn, William J. Kelly, Lisbeth Tranebjoerg, Claes MöllerAbstract:The aim was to define the natural history of hearing lossin Usher Syndrome type IIa compared to non-IIa. Peoplewith Usher Syndrome type II show moderate-to-severehearing loss, normal balance and retinitis pigmentosa.Several genes cause Usher Syndrome type II. Our subjectsformed two genetic groups: (1) subjects with Usher Syndrometype IIa with a mutation and/or linkage to theUsher IIa gene; (2) subjects with the Usher II phenotypewith no mutation and/or linkage to the Usher IIa gene.Four hundred and two audiograms of 80 Usher IIa subjectswere compared with 435 audiograms of 87 non-IIasubjects. Serial audiograms with intervals of ≥5 yearswere examined for progression in 109 individuals. Thosewith Usher Syndrome type IIa had significantly worsehearing thresholds than those with non-IIa Usher Syndromeafter the second decade. The hearing loss in UsherSyndrome type IIa was found to be more progressive, andthe progression started earlier than in non-IIa Usher Syndrome.This suggests an auditory phenotype for Ushe...
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Usher Syndrome : an otoneurologic study
Laryngoscope, 2009Co-Authors: Claes Möller, William J. Kimberling, S Davenport, Ira Priluck, Lars Ödkvist, V. White, K. Biscone-halterman, Patrick E. Brookhouser, Gunnar B. Lund, Timothy J. GrissomAbstract: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.
Claes Möller - One of the best experts on this subject based on the ideXlab platform.
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Life strategies of people with deafblindness due to Usher Syndrome type 2a - a qualitative study.
International Journal of Qualitative Studies on Health and Well-being, 2019Co-Authors: Agneta Anderzén-carlsson, Claes Möller, Moa WahlqvistAbstract:ABSTRACTPurpose: To explore life strategies in people with Usher Syndrome type 2a.Background: There are no studies on life strategies in people with Usher Syndrome. People with deafblindness are of...
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The prevalence of Usher Syndrome in Sweden: a nationwide epidemiological and clinical survey
Audiological Medicine, 2009Co-Authors: Mehdi Sadeghi, William J. Kimberling, Lisbeth Tranebjœrg, Claes MöllerAbstract:The purpose of this study was to estimate the prevalence of Usher Syndrome types I, II and III in Sweden and to estimate possible regional differences in the prevalence of different Usher Syndrome subtypes within the country. Probands were ascertained through multiple sources and almost complete ascertainment was achieved. A total of 370 subjects with a referring diagnosis of Usher was ascertained. Of those, 77 subjects proved to have an incorrect preliminary diagnosis. Of the remaining 293 individuals, 140 were found to have Usher Syndrome type I, 122 subjects were diagnosed as type II, and 27 subjects had Usher Syndrome type III. The corresponding prevalence in Sweden was estimated to be 1.6/100,000 for type I, 1.4/100.000 for type II and 0.3/100.000 for type III. The prevalence of Usher I was found to be significantly higher (8.6/100.000) in the two northernmost counties. This is consistent with an earlier report made in the 1950s. Similar geographic concentrations of Usher II and III were not observed...
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Audiological findings in Usher Syndrome types IIa and II (non-IIa)
International Journal of Audiology, 2009Co-Authors: Mehdi Sadeghi, William J. Kimberling, Edward S. Cohn, William J. Kelly, Lisbeth Tranebjoerg, Claes MöllerAbstract:The aim was to define the natural history of hearing lossin Usher Syndrome type IIa compared to non-IIa. Peoplewith Usher Syndrome type II show moderate-to-severehearing loss, normal balance and retinitis pigmentosa.Several genes cause Usher Syndrome type II. Our subjectsformed two genetic groups: (1) subjects with Usher Syndrometype IIa with a mutation and/or linkage to theUsher IIa gene; (2) subjects with the Usher II phenotypewith no mutation and/or linkage to the Usher IIa gene.Four hundred and two audiograms of 80 Usher IIa subjectswere compared with 435 audiograms of 87 non-IIasubjects. Serial audiograms with intervals of ≥5 yearswere examined for progression in 109 individuals. Thosewith Usher Syndrome type IIa had significantly worsehearing thresholds than those with non-IIa Usher Syndromeafter the second decade. The hearing loss in UsherSyndrome type IIa was found to be more progressive, andthe progression started earlier than in non-IIa Usher Syndrome.This suggests an auditory phenotype for Ushe...
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Usher Syndrome : an otoneurologic study
Laryngoscope, 2009Co-Authors: Claes Möller, William J. Kimberling, S Davenport, Ira Priluck, Lars Ödkvist, V. White, K. Biscone-halterman, Patrick E. Brookhouser, Gunnar B. Lund, Timothy J. GrissomAbstract: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.
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Usher Syndrome: Clinical findings and gene localization studies
Laryngoscope, 2009Co-Authors: William J. Kimberling, Michael D Weston, Claes Möller, S Davenport, Ira Priluck, V. White, K. Biscone-halterman, Gunnar B. Lund, Timothy J. Grissom, Patrick E. BrookhouserAbstract: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 indepth 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.
Elena Aller - One of the best experts on this subject based on the ideXlab platform.
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clinical aspects of Usher Syndrome and the ush2a gene in a cohort of 433 patients
JAMA Ophthalmology, 2015Co-Authors: Fiona Blancokelly, Teresa Jaijo, José M. Millán, Elena Aller, Almudena Avilafernandez, Blanca Garciasandoval, Maria Isabel Lopezmolina, Ascension Gimenez, Carmen AyusoAbstract:IMPORTANCE: A new statistical approach is needed to describe the clinical differences between type I and type II Usher Syndrome and between the 2 most frequent mutations in the USH2A gene. OBJECTIVES: To describe the primary phenotypic characteristics and differences between type I and type II Usher Syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher Syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES: Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss. RESULTS: The comparison between patients with type I Usher Syndrome and those with type II Usher Syndrome revealed P < .001 for most items analyzed. The most frequent mutations in the USH2A gene were the p.Glu767Serfs*21 and p.Cys759Phe mutations, with an allelic frequency of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. The phenotypic analysis for patients carrying p.Cys759Phe showed P < .001 for most items analyzed when compared with patients carrying p.Glu767Serfs*21 and when compared with patients carrying other mutations in the USH2A gene. None of the p.Cys759Phe patients exhibited a severe hearing loss phenotype, and more than 60% had only mild hearing loss. Most patients carrying the p.Glu767Serfs*21 mutation (72.1%) were moderately deaf. CONCLUSIONS AND RELEVANCE: Our study presents the clinical differences between type I and type II Usher Syndrome and between the 2 most frequent mutations in the USH2A gene. Detailed genotype-phenotype correlations, as presented in our study, allow for a better correlation of clinical signs with a known genotype and can improve the clinical management, genetic counseling, and risk assessment of patients with Usher Syndrome because an estimated prognosis of their disease can be made.
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Clinical aspects of Usher Syndrome and the USH2A gene in a cohort of 433 patients
JAMA Ophthalmology, 2015Co-Authors: Fiona Blanco-kelly, Teresa Jaijo, José M. Millán, Elena Aller, Ascension Gimenez, A Avila-fernandez, Maria Isabel Lopez-molina, Blanca Garcia-sandoval, Carmen AyusoAbstract:IMPORTANCE: A new statistical approach is needed to describe the clinical differences between type I and type II Usher Syndrome and between the 2 most frequent mutations in the USH2A gene. OBJECTIVES: To describe the primary phenotypic characteristics and differences between type I and type II Usher Syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher Syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES: Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss. RESULTS: The comparison between patients with type I Usher Syndrome and those with type II Usher Syndrome revealed P
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targeted next generation sequencing for molecular diagnosis of Usher Syndrome
Orphanet Journal of Rare Diseases, 2014Co-Authors: Elena Aller, Gema Garciagarcia, Maria Jose Aparisi, Regina Rodrigo, Carla Fustergarcia, Rafael P VazquezmanriqueAbstract:Background Usher Syndrome is an autosomal recessive disease that associates sensorineural hearing loss, retinitis pigmentosa and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous. To date, 10 genes have been associated with the disease, making its molecular diagnosis based on Sanger sequencing, expensive and time-consuming. Consequently, the aim of the present study was to develop a molecular diagnostics method for Usher Syndrome, based on targeted next generation sequencing.
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novel deletions involving the ush2a gene in patients with Usher Syndrome and retinitis pigmentosa
Molecular Vision, 2014Co-Authors: Gema Garciagarcia, Teresa Jaijo, Elena Aller, Maria Jose Aparisi, Fiona Blancokelly, Lise Larrieu, Annefrancoise Roux, Carmen Ayuso, Valerie Faugere, José M. MillánAbstract:Purpose The aim of the present work was to identify and characterize large rearrangements involving the USH2A gene in patients with Usher Syndrome and nonsyndromic retinitis pigmentosa.
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microarray based mutation analysis of 183 spanish families with Usher Syndrome
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Teresa Jaijo, Elena Aller, Gema Garciagarcia, Maria Jose Aparisi, Almudena Avilafernandez, Carmen Ayuso, Sara Bernal, Montserrat Baiget, Isabel Barragan, Guillermo AntinoloAbstract:PURPOSE: The purpose of this study was to test the ability of the genotyping microarray for Usher Syndrome (USH) to identify the mutations responsible for the disease in a cohort of 183 patients with USH. METHODS: DNA from 183 patients with Usher Syndrome from the Spanish population was analyzed using a genotyping microarray containing 429 previously identified disease-associated variants in eight USH genes. Mutations detected by the array were confirmed by direct sequencing. Haplotype analysis was also performed in families carrying common Spanish mutations. RESULTS: The genotyping microarray identified 43 different variants, divided into 32 disease causative and 11 probably nonpathologic. Mutations were detected in 62 patients with USH (33.9%). According to the clinical classification of patients, pathologic variants were detected in 31.4% patients with USH1, 39.4% of with USH2, 22.2% with USH3 and 15.8% with unclassified Usher Syndrome. Ninety-seven pathologic alleles were detected, corresponding to 26.5% of expected alleles. The USH2A mutations p.C3267R and p.T3571M were revealed as common in the Spanish population, and two major haplotypes linked to these mutations were observed. CONCLUSIONS: The genotyping microarray is a robust, low-cost, rapid technique that is effective for the genetic study of patients with USH. However, it also indicates variants of unclear pathologic nature and detection failures have also been observed. Results must be confirmed by direct sequencing to avoid misdiagnosis, and continuous updates of the microarray should be performed to increase the efficiency and rate of detection of mutations.
Michael D Weston - One of the best experts on this subject based on the ideXlab platform.
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Usher Syndrome: Clinical findings and gene localization studies
Laryngoscope, 2009Co-Authors: William J. Kimberling, Michael D Weston, Claes Möller, S Davenport, Ira Priluck, V. White, K. Biscone-halterman, Gunnar B. Lund, Timothy J. Grissom, Patrick E. BrookhouserAbstract: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 indepth 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.
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cdh23 mutation and phenotype heterogeneity a profile of 107 diverse families with Usher Syndrome and nonsyndromic deafness
American Journal of Human Genetics, 2002Co-Authors: L M Astuto, Julie M Bork, Randall R Fields, S J Ohliger, Michael D Weston, Dana J Orten, James W Askew, Robert J Morell, Saima Riazuddin, Shahid Y KhanAbstract: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.
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defective myosin viia gene responsible for Usher Syndrome type 1b
Nature, 1995Co-Authors: Dominique Well, Stephane Blanchard, Josseline Kaplan, Parry Guilford, James Walsh, Philomena Mburu, Anabel Varela, Jacqueline Levilliers, Fernando Gibson, Michael D WestonAbstract:Usher Syndrome represents the association of a hearing impairment with retinitis pigmentosa1 and is the most frequent cause of deaf–blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous2,3. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium)4–6, nasal ciliar cells7 and sperm cells5, as well as widespread degeneration of the organ of Corti8. Usher Syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH19–11,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients2,3. The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region12,13. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1(ref. 14) led us to consider the human homo-logue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH IB appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher Syndrome.
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Genetic heterogeneity of Usher Syndrome type II.
Journal of Medical Genetics, 1993Co-Authors: S. Pieke Dahl, Michael D Weston, William J. Kimberling, Michael B. Gorin, J. M R Furman, A. Pikus, Claes MöllerAbstract: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.
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linkage of Usher Syndrome type i gene ush1b to the long arm of chromosome 11
Genomics, 1992Co-Authors: William J. Kimberling, Michael D Weston, Claes Möller, S Davenport, I A Priluck, Peter Beighton, Jacquie Greenberg, William Reardon, J B Kenyon, J A GrunkemeyerAbstract: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.
José M. Millán - One of the best experts on this subject based on the ideXlab platform.
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clinical aspects of Usher Syndrome and the ush2a gene in a cohort of 433 patients
JAMA Ophthalmology, 2015Co-Authors: Fiona Blancokelly, Teresa Jaijo, José M. Millán, Elena Aller, Almudena Avilafernandez, Blanca Garciasandoval, Maria Isabel Lopezmolina, Ascension Gimenez, Carmen AyusoAbstract:IMPORTANCE: A new statistical approach is needed to describe the clinical differences between type I and type II Usher Syndrome and between the 2 most frequent mutations in the USH2A gene. OBJECTIVES: To describe the primary phenotypic characteristics and differences between type I and type II Usher Syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher Syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES: Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss. RESULTS: The comparison between patients with type I Usher Syndrome and those with type II Usher Syndrome revealed P < .001 for most items analyzed. The most frequent mutations in the USH2A gene were the p.Glu767Serfs*21 and p.Cys759Phe mutations, with an allelic frequency of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. The phenotypic analysis for patients carrying p.Cys759Phe showed P < .001 for most items analyzed when compared with patients carrying p.Glu767Serfs*21 and when compared with patients carrying other mutations in the USH2A gene. None of the p.Cys759Phe patients exhibited a severe hearing loss phenotype, and more than 60% had only mild hearing loss. Most patients carrying the p.Glu767Serfs*21 mutation (72.1%) were moderately deaf. CONCLUSIONS AND RELEVANCE: Our study presents the clinical differences between type I and type II Usher Syndrome and between the 2 most frequent mutations in the USH2A gene. Detailed genotype-phenotype correlations, as presented in our study, allow for a better correlation of clinical signs with a known genotype and can improve the clinical management, genetic counseling, and risk assessment of patients with Usher Syndrome because an estimated prognosis of their disease can be made.
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Clinical aspects of Usher Syndrome and the USH2A gene in a cohort of 433 patients
JAMA Ophthalmology, 2015Co-Authors: Fiona Blanco-kelly, Teresa Jaijo, José M. Millán, Elena Aller, Ascension Gimenez, A Avila-fernandez, Maria Isabel Lopez-molina, Blanca Garcia-sandoval, Carmen AyusoAbstract:IMPORTANCE: A new statistical approach is needed to describe the clinical differences between type I and type II Usher Syndrome and between the 2 most frequent mutations in the USH2A gene. OBJECTIVES: To describe the primary phenotypic characteristics and differences between type I and type II Usher Syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher Syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES: Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss. RESULTS: The comparison between patients with type I Usher Syndrome and those with type II Usher Syndrome revealed P
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novel deletions involving the ush2a gene in patients with Usher Syndrome and retinitis pigmentosa
Molecular Vision, 2014Co-Authors: Gema Garciagarcia, Teresa Jaijo, Elena Aller, Maria Jose Aparisi, Fiona Blancokelly, Lise Larrieu, Annefrancoise Roux, Carmen Ayuso, Valerie Faugere, José M. MillánAbstract:Purpose The aim of the present work was to identify and characterize large rearrangements involving the USH2A gene in patients with Usher Syndrome and nonsyndromic retinitis pigmentosa.
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mutation profile of the cdh23 gene in 56 probands with Usher Syndrome type i
Human Mutation, 2008Co-Authors: A Oshima, Teresa Jaijo, José M. Millán, Elena Aller, William J. Kimberling, Claes Möller, Carol Carney, Shinichi UsamiAbstract:Mutations in the human gene encoding cadherin 23 (CDH23) cause Usher Syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher Syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher Syndrome type I have CDH23 mutations.
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Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher Syndrome: low prevalence and phenotypic variability.
Clinical Genetics, 2004Co-Authors: Elena Aller, Teresa Jaijo, S Oltra, J Alió, F Galán, C. Nájera, Magdalena Beneyto, José M. MillánAbstract:Usher Syndrome type III is an autosomal recessive disorder clinically characterized by the association of retinitis pigmentosa (RP), variable presence of vestibular dysfunction and progressive hearing loss, being the progression of the hearing impairment the critical parameter classically used to distinguish this form from Usher Syndrome type I and Usher Syndrome type II. Usher Syndrome type III clinical subtype is the rarest form of Usher Syndrome in Spain, accounting only for 6% of all Usher Syndrome Spanish cases. The gene responsible for Usher Syndrome type III is named clarin-1 and it is thought to be involved in hair cell and photoreceptor cell synapses. Here, we report a screening for mutations in clarin-1 gene among our series of Usher Syndrome Spanish patients. Clarin-1 has been found to be responsible for the disease in only two families: the first one is a previously reported family homozygous for Y63X mutation and the second one, described here, is homozygous for C40G. This accounts for 1.7% of Usher Syndrome Spanish families. It is noticeable that, whereas C40G family is clinically compatible with Usher Syndrome type III due to the progression of the hearing loss, Y63X family could be diagnosed as Usher Syndrome type I because the hearing impairment is profound and stable. Thus, we consider that the progression of hearing loss is not the definitive key parameter to distinguish Usher Syndrome type III from Usher Syndrome type I and Usher Syndrome type II.
