RESUMEN
Hearing impairment affects about 1 in 1,000 children at birth. Approximately 70 loci implicated in non-syndromic forms of deafness have been reported in humans and 24 causative genes have been identified (see also http://www.uia.ac.be/dnalab/hhh). We report a mouse transcript, isolated by a candidate deafness gene approach, that is expressed almost exclusively in the inner ear. Genomic analysis shows that the human ortholog STRC (so called owing to the name we have given its protein-stereocilin), which is located on chromosome 15q15, contains 29 exons encompassing approximately 19 kb. STRC is tandemly duplicated, with the coding sequence of the second copy interrupted by a stop codon in exon 20. We have identified two frameshift mutations and a large deletion in the copy containing 29 coding exons in two families affected by autosomal recessive non-syndromal sensorineural deafness linked to the DFNB16 locus. Stereocilin is made up of 1,809 amino acids, and contains a putative signal petide and several hydrophobic segments. Using immunohistolabeling, we demonstrate that, in the mouse inner ear, stereocilin is expressed only in the sensory hair cells and is associated with the stereocilia, the stiff microvilli forming the structure for mechanoreception of sound stimulation.
Asunto(s)
Cromosomas Humanos Par 15/genética , Células Ciliadas Auditivas/metabolismo , Pérdida Auditiva Sensorineural/genética , Mutación/genética , Proteínas/genética , Secuencia de Aminoácidos , Animales , Preescolar , Mapeo Cromosómico , Clonación Molecular , Consanguinidad , Análisis Mutacional de ADN , Exones/genética , Perfilación de la Expresión Génica , Marcadores Genéticos/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular , Masculino , Proteínas de la Membrana , Ratones , Microscopía Fluorescente , Datos de Secuencia Molecular , Proteínas/química , ARN Mensajero/análisis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Secuencias Repetidas en Tándem/genéticaRESUMEN
We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.
Asunto(s)
Colágeno/genética , Pérdida Auditiva Sensorineural/genética , Mutación Missense , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Cromosomas Humanos Par 6/genética , ADN/genética , Modelos Animales de Enfermedad , Femenino , Genes Dominantes , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Hibridación in Situ , Masculino , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Linaje , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
The high temperatures and chemical composition, as determined by space probe and terrestrial observation, suggest that the present atmosphere of Venus has formed by chemical interaction with the lithosphere. Although the precise reactions have not been identified, good theoretical approximations to the molecular abundance may be obtained from reactions applicable to terrestial rocks. The high temperatures and chemical reactivity create conditions on Venus which are fundamentally different from those on the cooler terrestrial planets where the attainment of equilibrium is prevented by kinetic barriers.
RESUMEN
Genetic factors are the major causes of childhood hearing impairment. Whereas autosomal recessive mutations account for the majority of prelingual non-syndromic sensorineural hearing impairment (NSSHI), the relative contribution of mitochondrial DNA (mtDNA) mutations to childhood onset NSSHI has not been established. We screened 202 subjects with congenital/childhood onset NSSHI, consisting of 110 sporadic cases, 75 sib pairs, and 17 families with affected subjects in more than one generation, in order to determine the prevalence of mtDNA mutations associated with NSSHI.mtDNA mutations were found in three of 10 families (30%) in whom the affected members were related through the maternal lineage. One sporadic case (0.9%) was also found to have a known mtDNA mutation but none was found in the sib pairs. Although the prevalence of mtDNA mutations was low in the group as a whole (2%), we suggest that screening should be considered in cases of childhood hearing impairment when it is progressive and particularly in families where transmission is compatible with maternal inheritance.
Asunto(s)
ADN Mitocondrial/genética , Pérdida Auditiva Sensorineural/genética , Edad de Inicio , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Frecuencia de los Genes , Humanos , Masculino , Mutación , Linaje , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
We describe a family with non-syndromic sensorineural hearing impairment inherited in a manner consistent with maternal transmission. Affected members were found to have a novel heteroplasmic mtDNA mutation, T7510C, in the tRNA(Ser(UCN)) gene. This mutation was not found in 661 controls, is well conserved between species, and disrupts base pairing in the acceptor stem of the tRNA, making it the probable cause of hearing impairment in this family. Sequencing of the other mitochondrial tRNA genes did not show any other pathogenic mutations. Four other mutations causing hearing impairment have been reported in the tRNA(Ser(UCN)) gene, two having been shown to affect tRNA(Ser(UCN)) levels. With increasing numbers of reports of mtDNA mutations causing hearing impairment, screening for such mutations should be considered in all cases unless mitochondrial inheritance can be excluded for certain.
Asunto(s)
ADN Mitocondrial/genética , Pérdida Auditiva Sensorineural/genética , ARN de Transferencia de Serina/genética , Secuencia de Bases , Análisis Mutacional de ADN , ADN Mitocondrial/química , Salud de la Familia , Femenino , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Conformación de Ácido Nucleico , Linaje , Mutación Puntual , ARN de Transferencia de Serina/química , Alineación de Secuencia , Homología de Secuencia de Ácido NucleicoRESUMEN
Mutations in the human gap junction beta-2 gene (GJB2) that encodes connexin-26 have been shown to cause non-syndromic sensorineural hearing loss (NSSNHL) at the DFNB1 locus on 13q11. Functional and genetic data regarding the disease causing potential of one particular GJB2 sequence variant, 101 T-->C (M34T), have proven contradictory. In this study, we found the prevalence of the M34T allele in a cohort of white sib pairs and sporadic cases with NSSNHL from the United Kingdom and Ireland to be 3.179% of chromosomes screened. Significantly, we identified the first M34T/M34T genotype cosegregating in a single family with mid to high frequency NSSNHL. Screening a control population of 630 subjects we identified 25 M34T heterozygotes; however, no M34T homozygotes were detected. Surprisingly, the majority of M34T alleles (88%) were in cis with a 10 bp deletion in the 5' non-coding sequence. This non-coding deletion was also homozygous in the homozygous M34T subjects. Microsatellite analysis of flanking loci in M34T heterozygotes and controls does not define an extensive ancestral haplotype but preliminary data suggest two common alleles in subjects with the M34T allele. In summary, we provide data that support M34T acting as a recessive GJB2 allele associated with mild-moderate prelingual hearing impairment.
Asunto(s)
Conexinas/genética , Pérdida Auditiva Sensorineural/genética , Alelos , Sustitución de Aminoácidos , Secuencia de Bases , Segregación Cromosómica , Conexina 26 , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Frecuencia de los Genes , Pruebas Genéticas , Variación Genética , Genotipo , Pérdida Auditiva Sensorineural/diagnóstico , Homocigoto , Humanos , Masculino , Mutación , Linaje , Eliminación de SecuenciaRESUMEN
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
Despite the increasing number of reports of families with hearing impairment and mitochondrial DNA (mtDNA) mutations, the frequency of these mutations as causes of non-syndromic sensorineural hearing impairment (NSSHI) remains unknown. Mutations such as A1555G, A7445G and 7472insC have been found in several unrelated families implying they are more frequent than initially thought. We describe a family with NSSHI due to the presence of the homoplasmic mtDNA A7445G mutation in the tRNASer(UCN) gene. This is the fourth such family described with this mutation, all of different genetic backgrounds. Our study also demonstrates the difficulties sometimes encountered in establishing mitochondrial inheritance of hearing impairment in some families.
Asunto(s)
ADN Mitocondrial/genética , Sordera/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , ADN Mitocondrial/química , Sordera/patología , Salud de la Familia , Femenino , Humanos , Masculino , Linaje , Mutación PuntualRESUMEN
Several mtDNA mutations have been reported in families with both syndromic and non-syndromic hearing loss. One such mutation is the heteroplasmic 7472insC in the tRNA(Ser(UCN)) gene which has been found in six families, all from Western Europe. However, it was not clear if this distribution was due to a common founder effect or chance sampling of several unrelated families, the 7472insC mutation having occurred multiple times. Haplotype analysis of all six families supports the latter notion. This confirms the pathogenicity of the 7472insC mutation and suggests it may exist in other populations where it may prove to be a small but significant cause of hearing loss, particularly when neurological symptoms are also present.
Asunto(s)
ADN Mitocondrial/genética , Pérdida Auditiva Sensorineural/genética , Mutación , ARN de Transferencia de Serina/genética , ADN Mitocondrial/análisis , Demografía , Europa (Continente) , Haplotipos , Pérdida Auditiva Sensorineural/etnología , Humanos , SíndromeRESUMEN
Cerebral palsy (CP) has an incidence of approximately 1 in 750 births, although this varies between ethnic groups. Genetic forms of the disease account for about 2% of cases in most countries, but contribute a larger proportion in certain sub-types of the condition and in populations with a large proportion of consanguineous marriages. Ataxic cerebral palsy accounts for 5-10% of all forms of CP and it is estimated that approximately 50% of ataxic cerebral palsy is inherited as an autosomal recessive trait. We have identified a complex consanguineous Asian pedigree with four children in two sibships affected with ataxic cerebral palsy and have used homozygosity mapping to map the disorder in this family. A genome-wide search was performed using 343 fluorescently labelled polymorphic markers and linkage to chromosome 9p12-q12 was demonstrated. A maximum Lod score of 3.4 was observed between the markers D9S50 and D9S167 using multipoint analysis, a region of approximately 23cM. We have identified a family that segregates both ataxic CP and ataxic diplegia and have mapped the genetic locus responsible in this family to chromosome 9p12-q12. The identification of gene(s) involved in the aetiology of CP will offer the possibility of prenatal/premarital testing to some families with children affected with the disorder and will greatly increase our understanding of the development of the control of motor function.
Asunto(s)
Ataxia/patología , Parálisis Cerebral/genética , Cromosomas Humanos Par 9/genética , Alelos , Parálisis Cerebral/patología , Preescolar , Mapeo Cromosómico , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , LinajeRESUMEN
Non-syndromic sensorineural deafness is an extremely genetically heterogeneous condition. We have used autozygosity mapping in a large consanguineous United Arab Emirate family to identify a novel locus for autosomal recessive non-syndromic sensorineural deafness, DFNB27, on chromosome 2q23-q31, with a maximum two-point lod score of 5.18 at theta = 0 for marker D2S2257. The DFNB27 locus extends over a 17 cM region between D2S2157 and D2S2273, and may overlap the DFNA16 locus for dominantly inherited, fluctuating, progressive non-syndromal hearing loss. However, genotype data suggests that the locus is likely to be refined to between D2S326 and D2S2273 and thus distinct from the DFNA16 locus.
Asunto(s)
Cromosomas Humanos Par 2 , Pérdida Auditiva Sensorineural/genética , Mapeo Cromosómico , Consanguinidad , Femenino , Homocigoto , Humanos , Masculino , LinajeRESUMEN
We describe four affected children belonging to a large, highly inbred Muslim family originating from the North West Frontier Province of Pakistan. All children have a similar pattern of skeletal abnormalities, including aplasia/hypoplasia of the ulnae, hypoplasia of the pelvis, aplasia/hypoplasia of the femora, fibular aplasia, and variable digital abnormalities and absent/dysplastic nails. The phenotype overlaps with the syndromes of Fuhrmann, Al-Awadi, and Raas-Rothschild. The present and previously reported families probably share the same geographic and racial origin, indicating a common genetic basis of the reported skeletal abnormalities in these limb-pelvis aplasia and hypoplasia syndromes. A possibility of a new autosomal recessive syndrome in the present family cannot be excluded. Further delineation and molecular studies are required to clarify the genetic cause and phenotypic variation in Fuhrmann, Al-Awadi, and Raas-Rothschild syndromes.
Asunto(s)
Anomalías Múltiples/genética , Consanguinidad , Fémur/anomalías , Peroné/anomalías , Pelvis/anomalías , Cúbito/anomalías , Anomalías Múltiples/diagnóstico por imagen , Fémur/diagnóstico por imagen , Peroné/diagnóstico por imagen , Deformidades Congénitas del Pie/genética , Humanos , Lactante , Recién Nacido , Pakistán , Linaje , Pelvis/diagnóstico por imagen , Fenotipo , Radiografía , Síndrome , Cúbito/diagnóstico por imagenRESUMEN
Two major types of chondrodysplasia punctata have been delineated; a severe, recessively inherited, rhizomelic form and the less severe, dominantly inherited Conradi-Hünerman form. Clinico-genetic analysis of this latter form of CP uncovered a sub-group characterised by asymmetric involvement with linear or whorled skin patches of ichthyosiform erythroderma or atrophoderma, circumscribed cicatricial alopecia, asymmetrical cataracts and limb shortness. The mosaic pattern of the manifestations and the limitation of reported cases to females suggested an X-linked dominant gene which undergoes Lyonisation in the female and is lethal in the hemizygous male. We report on a family ascertained through a baby girl who had manifestations typical of the X-linked dominant form of CP and whose mother, 2 of 3 maternal aunts, and maternal grandmother all had less severe manifestations. The absence of male offspring for 3 generations and a history of 3 early miscarriages, along with the clinical variability in the affected females, provide further support for X-linked dominant inheritance of this disorder.
Asunto(s)
Condrodisplasia Punctata/genética , Preescolar , Femenino , Ligamiento Genético , Humanos , Masculino , Linaje , Cromosoma XRESUMEN
To date, 32 cases of partial 7p monosomy have been described, 14 of which have been associated with craniosynostosis (CRS). There is considerable variation in the size and location of the deleted segment. However, CRS appears to be consistently associated with either a deletion or partial deletion 7p21-->7p22 or more rarely a deletion of 7p13-->7p14. Analysis of a panel of six 7p deletion cases (three with CRS) was undertaken using informative DNA probes, in order to characterize and define the extent of the deletions at the molecular level. There were five de novo deletions and one resulting from the unbalanced product of a paternal balanced insertion. The putative proximal CRS locus at 7p13-->7p14 does not appear to be allelic with Greig cephalopolysyndactyly syndrome. Three probe positions have been refined: pJ5.11 (D7S10) previously mapped to 7p14-->pter does not appear to map proximal to p15; TM102L (D7S135) does not map distal to p22; CRI-P137 (D7S65) maps distal to 7p13.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 7 , Craneosinostosis/genética , Sindactilia/genética , Bandeo Cromosómico , Desoxirribonucleasa HpaII , Desoxirribonucleasas de Localización Especificada Tipo II , Femenino , Humanos , Masculino , Polimorfismo de Longitud del Fragmento de Restricción , Mapeo Restrictivo , Cráneo/anomalías , SíndromeRESUMEN
In some chorionic villus biopsy (CVB) cases the fetal/maternal origin of the tissue obtained is uncertain. An approach which only requires small amounts of CVB tissue to establish its origin is described. Since it is only the samples typed as female that could be either fetal or maternal, a paternal X chromosome contribution is sought by using highly polymorphic X-linked microsatellites.
Asunto(s)
Muestra de la Vellosidad Coriónica , ADN Satélite/genética , Reacción en Cadena de la Polimerasa/métodos , Alelos , Dermatoglifia del ADN , Sondas de ADN , Estudios de Evaluación como Asunto , Padre , Femenino , Feto , Marcadores Genéticos , Humanos , Madres , Polimorfismo Genético , Embarazo , Cromosoma XRESUMEN
BACKGROUND: Nonsyndromic hearing loss (NSHL) is the most common type of hereditary hearing impairment (HHI). It is genetically heterogeneous, and although the exact number of genes is not known, 38 loci have been identified. By cloning the relevant genes and studying the function of the encoded proteins at the molecular level, it may be possible to impact the habitation of persons at risk for HHI. Currently, for select families, presymptomatic diagnosis of NSHL by genotyping is possible. OBJECTIVE: To provide presymptomatic diagnosis of HHI to individuals in select families who have participated in linkage studies. DESIGN: In 2 large families with autosomal dominant HHI, genes for NSHL were mapped to chromosomes 6 (DFNA10) and 19 (DFNA4). In each family, the phenotype is one of progressive sensorineural hearing loss that begins in the individual's mid-30s and progresses to a severe-to-profound loss requiring amplification. Presymptomatic diagnosis was requested by, and provided to, 19 at-risk persons in these kindreds. RESULTS: By reconstructing haplotypes through the use of short tandem repeat polymorphisms tightly linked to the disease gene, risk calculations and genetic counseling were provided to these persons. CONCLUSIONS: By simple Mendelian genetics, the risk of inheriting a fully penetrant autosomal dominant NSHL gene from a single affected parent is 50% for each offspring. However, by reconstructing haplotypes in families in which an HHI gene has been localized, this risk can be changed substantially.