RESUMEN
Myosin VIIA mutations have been associated with non-syndromic hearing loss (DFNB2; DFNA11) and Usher syndrome type 1B (USH1B). We report clinical and genetic analyses of a consanguineous Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL). The hearing impairment was mapped to the DFNB2 locus using Affymetrix 50K GeneChips; direct sequencing of the MYO7A gene was completed. The Iranian family (L-1419) was shown to segregate a novel homozygous missense mutation (c.1184G>A) that results in a p.R395H amino acid substitution in the motor domain of the myosin VIIA protein. As one affected family member had significantly less severe hearing loss, we used a candidate approach to search for a genetic modifier. This novel MYO7A mutation is the first reported to cause DFNB2 in the Iranian population and this DFNB2 family is the first to be associated with a potential modifier. The absence of vestibular and retinal defects, and less severe low frequency hearing loss, is consistent with the phenotype of a recently reported Pakistani DFNB2 family. Thus, we conclude this family has non-syndromic hearing loss (DFNB2) rather than USH1B, providing further evidence that these two diseases represent discrete disorders.
Asunto(s)
Pérdida Auditiva/genética , Mutación Missense , Miosinas/genética , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Consanguinidad , Familia , Femenino , Pérdida Auditiva Sensorineural/genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Miosina VIIaRESUMEN
Usher Syndrome (US), an autosomal recessive disease, is characterized by retinitis pigmentosa (RP), vestibular dysfunction, and congenital sensorineural deafness. There are three recognized clinical types of the disorder. In order to improve genetic counseling for affected families, we conducted linkage analysis and DNA sequencing in 10 Colombian families with confirmed diagnosis of US (4 type I and 6 type II). Seventy-five percent of the US1 families showed linkage to locus USH1B, while the remaining 25% showed linkage to loci USH1B and USH1C. Among families showing linkage to USH1B we found two different mutations in the MYO7A gene: IVS42-26insTTGAG in exon 43 (heterozygous state) and R634X (CGA-TGA) in exon 16 (homozygous state). All six US2 families showed linkage to locus USH2A. Of them, 4 had c.2299delG mutation (1 homozygote state and 3 heterozygous); in the remaining 2 we did not identify any pathologic DNA variant. USH2A individuals with a 2299delG mutation presented a typical and homogeneous retinal phenotype with bilateral severe hearing loss, except for one individual with a heterozygous 2299delG mutation, whose hearing loss was asymmetric, but more profound than in the other cases. The study of these families adds to the genotype-phenotype characterization of the different types and subtypes of US and facilitates genetic counseling in these families. We would like to emphasize the need to perform DNA studies as a prerequisite for genetic counseling in affected families.
Asunto(s)
Dineínas/genética , Asesoramiento Genético , Ligamiento Genético/genética , Miosinas/genética , Mutación Puntual/genética , Síndromes de Usher/genética , Adolescente , Adulto , Anciano , Colombia/epidemiología , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miosina VIIa , Linaje , Retinitis Pigmentosa/genética , Índice de Severidad de la Enfermedad , Síndromes de Usher/epidemiologíaRESUMEN
Mutations in the human gene encoding cadherin23 (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.
Asunto(s)
Cadherinas/genética , Mutación , Síndromes de Usher/genética , Proteínas Relacionadas con las Cadherinas , Cadherinas/química , Análisis Mutacional de ADN , Dineínas/genética , Exones , Humanos , Mutación Missense , Miosina VIIa , Miosinas/genética , Estructura Terciaria de Proteína , España , Suecia , Estados UnidosRESUMEN
INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.
Asunto(s)
Conexinas/genética , Pérdida Auditiva/genética , Proteínas de la Membrana/genética , Mutación , Niño , Mapeo Cromosómico , Conexina 26 , Familia , Femenino , Variación Genética , Genotipo , Humanos , MasculinoAsunto(s)
Genes Recesivos/genética , Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , SíndromeAsunto(s)
Pérdida Auditiva Sensorineural/genética , Audiometría , Proteínas de la Matriz Extracelular/genética , Genotipo , Pérdida Auditiva Sensorineural/clasificación , Pérdida Auditiva Sensorineural/diagnóstico , Humanos , Mutación , Fenotipo , Retinitis Pigmentosa/genética , Síndrome , Enfermedades Vestibulares/genéticaRESUMEN
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.
Asunto(s)
Cadherinas/genética , Sordera/genética , Mutación , Retinitis Pigmentosa/genética , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Proteínas Relacionadas con las Cadherinas , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Heterogeneidad Genética , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Fenotipo , Alineación de Secuencia , Síndrome , Pruebas de Función VestibularAsunto(s)
Audiometría , Sordera/genética , Proteínas de la Matriz Extracelular/genética , Retinitis Pigmentosa/genética , Enfermedades Vestibulares/genética , Adulto , Alelos , Audiometría/métodos , Sordera/diagnóstico , Femenino , Ligamiento Genético/genética , Marcadores Genéticos/genética , Humanos , Masculino , Linaje , Retinitis Pigmentosa/diagnóstico , Síndrome , Enfermedades Vestibulares/diagnósticoRESUMEN
Usher syndrome is an autosomal recessively inherited disease, characterised by sensorineural hearing loss, tapetoretinal degeneration and in some cases vestibular problems. Based on the clinical heterogeneity, the disease can be classified into three clinical types (I, II and III), which have their own genetic subtypes (Usher 1A-Usher IG, Usher 2A-Usher 2C and Usher 3). The majority of the Usher type I cases are caused by mutations in the MYO7A gene (Usher 1B) while mutations in the USH2A gene (Usher 2A) are the cause of most cases of type II. Usher syndrome type III, caused by mutations in the USH3 gene, is frequently seen only in Finland.
Asunto(s)
Pérdida Auditiva Sensorineural/genética , Retinitis Pigmentosa/genética , Enfermedades Vestibulares/genética , Genes Recesivos , Humanos , Mutación , Linaje , SíndromeRESUMEN
We report a high prevalence of GJB2 heterozygous mutations in patients bearing the 1555A-->G mitochondrial mutation, and describe a family in which potential interaction between GJB2 and a mitochondrial gene appears to be the cause of hearing impairment. Patients who are heterozygotes for the GJB2 mutant allele show hearing loss more severe than that seen in sibs lacking a mutant GJB2 allele, suggesting that heterozygous GJB2 mutations may synergistically cause hearing loss when in the presence of a 1555A-->G mutation. The present findings indicate that GJB2 mutations may sometimes be an aggravating factor, in addition to aminoglycoside antibiotics, in the phenotypic expression of the non-syndromic hearing loss associated with the 1555A-->G mitochondrial mutation.
Asunto(s)
Conexinas/genética , ADN Mitocondrial/genética , Pérdida Auditiva de Alta Frecuencia/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Conexina 26 , Análisis Mutacional de ADN , Frecuencia de los Genes , Genotipo , Pérdida Auditiva de Alta Frecuencia/epidemiología , Pérdida Auditiva Sensorineural/epidemiología , Heterocigoto , Humanos , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Mutation analysis of the PDS gene and the EYA1 gene, which are reported to be responsible for hearing loss associated with ear anomalies, was performed in 24 deaf patients with various middle and inner ear anomalies. The present study was done to clarify the spectrum of middle and inner ear malformations covered by these two genes. PDS mutations were found only in patients with enlarged vestibular aqueducts and EYA1 mutations were detected only in patients with ear pits and cervical fistulae, indicating that these two genes are associated with particular forms of middle and inner ear malformation. The genetic approach provides a strong tool for the diagnosis of hearing loss associated with ear anomalies.
Asunto(s)
Proteínas Portadoras/genética , Anomalías Congénitas/genética , Sordera/genética , Oído/anomalías , Proteínas de Transporte de Membrana , Mutación , Transactivadores/genética , Adolescente , Adulto , Niño , Análisis Mutacional de ADN , Sordera/etiología , Femenino , Genes Dominantes , Genes Recesivos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Proteínas Nucleares , Proteínas Tirosina Fosfatasas , Transportadores de SulfatoRESUMEN
Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied, most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for autosomal dominant sensorineural hearing loss. The present study reports that a mutation in KCNQ4, a member of a large family of potassium channel genes, was responsible for ADSNHL in one Japanese family.
Asunto(s)
Genes Dominantes/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Adolescente , Adulto , Anciano , Audiometría , Secuencia de Bases , Niño , Preescolar , Conexinas/genética , Análisis Mutacional de ADN , Dineínas , Exones/genética , Femenino , Genotipo , Humanos , Japón , Canales de Potasio KCNQ , Masculino , Persona de Mediana Edad , Mutación , Miosina VIIa , Miosinas/genética , Linaje , Fenotipo , Polimorfismo Genético/genéticaRESUMEN
Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis pigmentosa. The mutation that most commonly causes Usher syndrome type IIa is a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identified in several patients from northern and southern Europe and from North America, and it has been found in single patients from South America, South Africa, and China. Various studies have reported a range of frequencies (.16-.44) among patients with Usher syndrome, depending on the geographic origin of the patients. The 2299delG mutation may be the one that most frequently causes retinitis pigmentosa in humans. Given the high frequencies and the wide geographic distribution of the mutation, it was of interest to determine whether the mutation resulted from an ancestral mutational event or represented a mutational hotspot in the USH2A gene. Haplotype analysis was performed on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of six single-nucleotide polymorphisms within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in our analysis, only one core haplotype was found to be associated with the 2299delG mutation. The data indicate that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that has spread throughout Europe and into the New World as a result of migration.
Asunto(s)
Sordera/genética , Proteínas de la Matriz Extracelular/genética , Efecto Fundador , Frecuencia de los Genes/genética , Retinitis Pigmentosa/genética , Eliminación de Secuencia/genética , Alelos , Evolución Molecular , Pruebas Genéticas , Genotipo , Geografía , Haplotipos/genética , Humanos , Repeticiones de Microsatélite/genética , Mutagénesis/genética , Polimorfismo de Nucleótido Simple/genética , SíndromeRESUMEN
Usher syndrome (USH) is a combination of a progressive pigmentary retinopathy, indistinguishable from retinitis pigmentosa, and some degree of sensorineural hearing loss. USH can be subdivided in Usher type I (USHI), type II (USHII) and type III (USHIII), all of which are inherited as autosomal recessive traits. The three subtypes are genetically heterogeneous, with six loci so far identified for USHI, three for USHII and only one for USHIII. Mutations in a novel gene, USH2A, encoding the protein usherin, have recently been shown to be associated with USHII. The gene encodes a protein with partial sequence homology to both laminin epidermal growth factor and fibronectin motifs. We analysed 35 British and one Pakistani Usher type II families with at least one affected member, for sequence changes in the 20 translated exons of the USH2A gene, using heteroduplex analysis and sequencing. Probable disease-causing mutations in USH2A were identified in 15 of 36 (41.7%) Usher II families. The most frequently encountered mutation (11/15 families or 11/18 mutated alleles) was del2299G in exon 13, resulting in a frameshift and premature stop codon. Other mutations include insertions and point mutations, of which two are previously unreported. Five different polymorphisms were also detected. Our results indicate that mutations in this gene are responsible for disease in a large proportion of British Usher type II patients. Moreover, if screening for mutations in USH2A is considered, it is sensible to screen for the del2299G mutation first.
Asunto(s)
Pérdida Auditiva Sensorineural/genética , Mutación/genética , Retinitis Pigmentosa/genética , Deleción Cromosómica , Femenino , Mutación del Sistema de Lectura/genética , Genes Recesivos , Ligamiento Genético/genética , Análisis Heterodúplex , Humanos , Masculino , Linaje , Mutación Puntual/genética , Polimorfismo Genético , SíndromeRESUMEN
OBJECTIVES: Usher's syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and progressive visual loss secondary to retinitis pigmentosa. Usher's syndrome is both clinically and genetically heterogeneous. Three clinical types are known today. METHODS: We conducted a study on 74 patients with Usher's syndrome, performing complete audiological and neurotological examinations. RESULTS: Twenty-six patients had total profound hearing loss and retinitis pigmentosa (Usher's syndrome type I), and 48 patients had moderate to severe sensorineural hearing loss and retinitis pigmentosa (Usher's syndrome type II). We identified 9 of the 26 Usher's syndrome patients with profound hearing loss who showed a normal response to bithermal vestibular testing. CONCLUSIONS: The combination of profound hearing loss and normal response to bithermal vestibular testing has not been previously described in Usher's syndrome. Therefore we describe a new subtype of Usher's syndrome type I and suggest a modified clinical classification for Usher's syndrome.
Asunto(s)
Pérdida Auditiva Sensorineural/clasificación , Retinitis Pigmentosa/clasificación , Adulto , Factores de Edad , Audiometría de Tonos Puros , Sordera/clasificación , Sordera/genética , Potenciales Evocados Auditivos/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Genes Recesivos/genética , Pérdida Auditiva Sensorineural/genética , Humanos , Persona de Mediana Edad , Nistagmo Fisiológico , Retinitis Pigmentosa/genética , Síndrome , Pruebas de Función Vestibular , Vestíbulo del Laberinto/fisiopatología , Trastornos de la Visión/clasificación , Trastornos de la Visión/genéticaRESUMEN
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.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 10/genética , Sordera/genética , Heterogeneidad Genética , Retinitis Pigmentosa/genética , Mapeo Cromosómico , Consanguinidad , Análisis Mutacional de ADN , Genes Recesivos/genética , Humanos , Escala de Lod , Mutación/genética , SíndromeRESUMEN
Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigmentosa from the late teens. Mutations in the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have investigated the molecular pathology of Usher type II by screening the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway. Besides the frequent 2299delG mutation, which accounted for 44% of the disease alleles, a heterogeneous spectrum of mutations was identified. Sixteen new, putative disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-pathogenic polymorphisms were identified. All missense mutations resulted in major amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the laminin-type epidermal growth factor-like (LE) domain. The structural consequences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma1 chain.
Asunto(s)
Sordera/genética , Proteínas de la Matriz Extracelular/genética , Retinitis Pigmentosa/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Cartilla de ADN/química , Proteínas de la Matriz Extracelular/química , Variación Genética , Humanos , Laminina/química , Laminina/metabolismo , Modelos Moleculares , Modelos Estructurales , Datos de Secuencia Molecular , Mutación Missense , Conformación Proteica , Homología de Secuencia de Aminoácido , SíndromeRESUMEN
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.
Asunto(s)
Sordera/genética , Discapacidad Intelectual/genética , Retinitis Pigmentosa/genética , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Sordera/epidemiología , Trastornos Neurológicos de la Marcha/epidemiología , Trastornos Neurológicos de la Marcha/genética , Humanos , Discapacidad Intelectual/epidemiología , Miosinas/genética , Retinitis Pigmentosa/epidemiología , Síndrome , Estados Unidos/epidemiologíaAsunto(s)
ADN Mitocondrial/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Femenino , Humanos , Masculino , Linaje , Mutación PuntualRESUMEN
Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder with variable clinical manifestations. The most common features of BOR syndrome are branchial, hearing, and renal anomalies. However, many affected subjects have been observed with branchial-cleft anomalies and hearing loss but without renal anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to question whether the BOR and BO syndromes are allelic or whether they represent distinct genetic entities. We identified a very large extended family whose members had branchial and hearing anomalies associated with commissural lip pits that segregated in an autosomal dominant fashion. Using a genomewide search strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757 in the genetic region of chromosome 1q31. This is the first report of linkage for a second gene associated with BOR syndrome. The findings have important clinical implications and will provide insight into the genetic basis of BOR syndrome.