RESUMEN
Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder effect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for different single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant differences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder.
Asunto(s)
Conexinas/genética , Pérdida Auditiva Sensorineural/genética , Alelos , Conexina 26 , ADN/química , ADN/genética , Análisis Mutacional de ADN , Efecto Fundador , Frecuencia de los Genes , Genotipo , Humanos , Mutación , Polimorfismo de Nucleótido Simple , Eliminación de SecuenciaRESUMEN
INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.
Asunto(s)
Conexinas/genética , Pérdida Auditiva/genética , Pérdida Auditiva/fisiopatología , Mutación/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Envejecimiento , Alelos , Audiometría , Bélgica , Niño , Preescolar , Conexina 26 , Análisis Mutacional de ADN , Progresión de la Enfermedad , Pruebas Genéticas , Genotipo , Pérdida Auditiva/clasificación , Humanos , Lactante , Italia , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , España , Estados UnidosRESUMEN
Mutations in GJB2 are the most common cause of hereditary congenital hearing loss in many countries and are found in about half of persons with severe-to-profound congenital autosomal recessive non-syndromic hearing loss (ARNSHL). We report the results of GJB2 mutation screening in 209 consecutive persons with congenital deafness of indeterminate etiology using an allele-specific polymerase chain reaction assay, single-strand conformational polymorphism analysis, and direct sequencing. GJB2 allele variants were detected in 74 of 209 deaf individuals (35%). Over one-fourth of screened individuals were either homozygous (n=31) or heterozygous (n=24) for the 35delG mutation. Of those with the 35delG mutation, 51 (92.7%) were diagnosed with GJB2-related deafness. Nineteen persons were identified with other GJB2 allele variants - two novel deafness-causing mutations (R32C, 645-648delTAGA), one mutation of unknown significance (E47K), and one benign polymorphism (I128I). While these data enable health care professionals to provide parents and patients with improved genetic counseling data, difficulty still exists is determining whether some missense mutations compromise auditory function and are deafness-causing.
Asunto(s)
Alelos , Conexinas/genética , Sordera/genética , Variación Genética , Pérdida Auditiva Sensorineural/genética , Mutación/genética , Sustitución de Aminoácidos/genética , Arginina/genética , Conexina 26 , Conexinas/sangre , Cisteína/genética , Sordera/congénito , Sordera/diagnóstico , Pruebas Genéticas/métodos , Pérdida Auditiva Sensorineural/congénito , Pérdida Auditiva Sensorineural/diagnóstico , Humanos , Eliminación de Secuencia/genéticaRESUMEN
Mutations in PDS (SLC26A4) cause both Pendred syndrome and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. The hearing loss is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct (dilated vestibular aqueduct, DVA) to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2(1/2) turns is replaced by a hypoplastic coil of 1(1/2) turns. In Pendred syndrome, thyromegaly also develops, although affected persons usually remain euthyroid. We identified PDS mutations in the proband of 14 of 47 simplex families (30%) and nine of 11 multiplex families (82%) (P=0.0023). In all cases, mutations segregated with the disease state in multiplex families. Included in the 15 different PDS allele variants we found were eight novel mutations. The two most common mutations, T416P and IVS8+1G>A, were present in 22% and 30% of families, respectively. The finding of PDS mutations in five of six multiplex families with DVA (83%) and four of five multiplex families with Mondini dysplasia (80%) implies that mutations in this gene are the major genetic cause of these temporal anomalies. Comparative analysis of phenotypic and genotypic data supports the hypothesis that the type of temporal bone anomaly may depend on the specific PDS allele variant present.
Asunto(s)
Anomalías Múltiples/genética , Proteínas Portadoras/genética , Sordera/genética , Proteínas de Transporte de Membrana , Mutación/genética , Anomalías Múltiples/fisiopatología , Alelos , Southern Blotting , Niño , Preescolar , Análisis Mutacional de ADN , Sordera/fisiopatología , Exones/genética , Familia , Genes Recesivos/genética , Pruebas Genéticas , Genotipo , Humanos , Lactante , Mutación Missense/genética , Fenotipo , Transportadores de Sulfato , Síndrome , Hueso Temporal/anomalías , Acueducto Vestibular/anomalíasRESUMEN
GJB2 encodes the protein Connexin 26, one of the building blocks of gap junctions. Each Connexin 26 molecule can oligomerize with five other connexins to form a connexon; two connexons, in turn, can form a gap junction. Because mutations in GJB2 are the most common cause of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss, the effect of the Connexin 26 allele variants on this dynamic 'construction' process and the function of any gap junctions that do form is particularly germane. One of the more controversial allele variants, M34T, has been hypothesized to cause autosomal dominant nonsyndromic hearing loss. In this paper, we present clinical and genotypic data that refutes this hypothesis and suggests that the effect of the M34T allele variant may be dependent on the mutations segregating in the opposing allele.