RESUMEN
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
Asunto(s)
Redes Reguladoras de Genes , Mutación , Corteza Prefrontal/embriología , Mapas de Interacción de Proteínas , Esquizofrenia/genética , Esquizofrenia/metabolismo , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Humanos , Masculino , Neurogénesis , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Esquizofrenia/fisiopatología , Transcripción Genética , TranscriptomaRESUMEN
The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For the great majority (87%) of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites. Genetic heterogeneity of hearing loss was striking with respect to both genes and alleles: The 337 solved families harbored 143 different mutations in 48 different genes. For one in four solved families, a transcription-altering mutation was the responsible allele. Many of these mutations were cryptic, either exonic alterations of splice enhancers or silencers or deeply intronic events. Experimentally calibrated in silico analysis of transcriptional effects yielded inferences of high confidence for effects on splicing even of mutations in genes not expressed in accessible tissue. Most (58%) of all hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation.
Asunto(s)
Pérdida Auditiva/congénito , Pérdida Auditiva/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Consanguinidad , Exones , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Medio Oriente , Mutación , Linaje , Adulto JovenRESUMEN
Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.
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Temblor Esencial/genética , Mitocondrias/enzimología , Proteínas Mitocondriales/genética , Enfermedad de Parkinson/genética , Serina Endopeptidasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Serina Peptidasa A2 que Requiere Temperaturas Altas , Humanos , Masculino , Persona de Mediana Edad , Linaje , Adulto JovenRESUMEN
Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.
Asunto(s)
Agenesia del Cuerpo Calloso/genética , Quistes Aracnoideos/genética , Encefalopatías/genética , Encéfalo/anomalías , Pérdida Auditiva Sensorineural/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Adolescente , Adulto , Agenesia del Cuerpo Calloso/patología , Quistes Aracnoideos/patología , Encéfalo/patología , Niño , Preescolar , Salud de la Familia , Femenino , Eliminación de Gen , Pérdida Auditiva Sensorineural/patología , Homocigoto , Humanos , Lactante , Masculino , Análisis de Secuencia de ADNRESUMEN
Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Here we present OTOGL mutations, a homozygous one base pair deletion (c.1430 delT) causing a frameshift (p.Val477Glufs(∗)25) in a large consanguineous family and two compound heterozygous mutations, c.547C>T (p.Arg183(∗)) and c.5238+5G>A, in a nonconsanguineous family with moderate nonsyndromic sensorineural hearing loss. OTOGL maps to the DFNB84 locus at 12q21.31 and encodes otogelin-like, which has structural similarities to the epithelial-secreted mucin protein family. We demonstrate that Otogl is expressed in the inner ear of vertebrates with a transcription level that is high in embryonic, lower in neonatal, and much lower in adult stages. Otogelin-like is localized to the acellular membranes of the cochlea and the vestibular system and to a variety of inner ear cells located underneath these membranes. Knocking down of otogl with morpholinos in zebrafish leads to sensorineural hearing loss and anatomical changes in the inner ear, supporting that otogelin-like is essential for normal inner ear function. We propose that OTOGL mutations affect the production and/or function of acellular structures of the inner ear, which ultimately leads to sensorineural hearing loss.
Asunto(s)
Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación , Adolescente , Animales , Preescolar , Aberraciones Cromosómicas , Cóclea/metabolismo , Cóclea/patología , Exoma , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Pérdida Auditiva Sensorineural/diagnóstico , Humanos , Mutación INDEL , Masculino , Ratones , Polimorfismo de Nucleótido Simple , Ratas , Pez CebraRESUMEN
Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss.
Asunto(s)
Pérdida Auditiva/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Animales , Polaridad Celular , Codón sin Sentido , Consanguinidad , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Estudios de Asociación Genética , Células Ciliadas Auditivas/metabolismo , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , MutaciónRESUMEN
Age-related hearing loss is due to death over time, primarily by apoptosis, of hair cells in the inner ear. Studies of mutant genes responsible for inherited progressive hearing loss have suggested possible mechanisms for hair cell death, but critical connections between these mutations and the causes of progressive hearing loss have been elusive. In an Israeli kindred, dominant, adult-onset, progressive nonsyndromic hearing loss DFNA51 is due to a tandem inverted genomic duplication of 270 kb that includes the entire wild-type gene encoding the tight junction protein TJP2 (ZO-2). In the mammalian inner ear, TJP2 is expressed mainly in tight junctions, and also in the cytoplasm and nuclei. TJP2 expression normally decreases with age from embryonic development to adulthood. In cells of affected family members, TJP2 transcript and protein are overexpressed, leading to decreased phosphorylation of GSK-3beta and to altered expression of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3beta-mediated increased susceptibility to apoptosis of cells of the inner ear is the mechanism for adult-onset hearing loss in this kindred and may serve as one model for age-related hearing loss in the general population.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Pérdida Auditiva/genética , Proteínas de la Membrana/genética , Uniones Estrechas/metabolismo , Animales , Oído Interno/embriología , Oído Interno/crecimiento & desarrollo , Oído Interno/metabolismo , Duplicación de Gen , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Pérdida Auditiva/metabolismo , Humanos , Proteínas de la Membrana/biosíntesis , Ratones , Linaje , Fosforilación , Proteína de la Zonula Occludens-2RESUMEN
More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown autosomal-recessive nonsyndromic sensorineural hearing loss locus (DFNB91) to chromosome 6p25 in a consanguineous Turkish family. The degree of hearing loss was moderate to severe in affected individuals. We subsequently identified a nonsense mutation (p.E245X) in SERPINB6, which is located within the linkage interval for DFNB91 and encodes for an intracellular protease inhibitor. The p.E245X mutation cosegregated in the family as a completely penetrant autosomal-recessive trait and was absent in 300 Turkish controls. The mRNA expression of SERPINB6 was reduced and production of protein was absent in the peripheral leukocytes of homozygotes, suggesting that the hearing loss is due to loss of function of SERPINB6. We also demonstrated that SERPINB6 was expressed primarily in the inner ear hair cells. We propose that SERPINB6 plays an important role in the inner ear in the protection against leakage of lysosomal content during stress and that loss of this protection results in cell death and sensorineural hearing loss.
Asunto(s)
Codón sin Sentido , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Mutación , Serpinas/genética , Consanguinidad , Familia , Herencia , Homocigoto , HumanosRESUMEN
Calcium oxalate stone formation occurs under pathological conditions and accounts for more than 80% of all types of kidney stones. In the current study, we show for the first time that calcium oxalate stones are formed in the mouse inner ear of a genetic model for hearing loss and vestibular dysfunction in humans. The vestibular system within the inner ear is dependent on extracellular tiny calcium carbonate minerals for proper function. Thousands of these biominerals, known as otoconia, are associated with the utricle and saccule sensory maculae and are vital for mechanical stimulation of the sensory hair cells. We show that a missense mutation within the Slc26a4 gene abolishes the transport activity of its encoded protein, pendrin. As a consequence, dramatic changes in mineral composition, size, and shape occur within the utricle and saccule in a differential manner. Although abnormal giant carbonate minerals reside in the utricle at all ages, in the saccule, a gradual change in mineral composition leads to a formation of calcium oxalate in adult mice. By combining imaging and spectroscopy tools, we determined the profile of mineral composition and morphology at different time points. We propose a novel mechanism for the accumulation and aggregation of oxalate crystals in the inner ear.
Asunto(s)
Oxalato de Calcio/química , Proteínas de Transporte de Membrana/genética , Mutación Missense , Secuencia de Aminoácidos , Animales , Proteínas de Transporte de Anión/metabolismo , Cóclea/patología , Sordera/genética , Oído Interno/patología , Matriz Extracelular/metabolismo , Células Ciliadas Auditivas/metabolismo , Humanos , Ratones , Microscopía Electrónica de Rastreo/métodos , Datos de Secuencia Molecular , Ratas , Homología de Secuencia de Aminoácido , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman/métodos , Transportadores de SulfatoRESUMEN
The motor protein myosin IIIA is critical for maintenance of normal hearing. Homozygosity and compound heterozygosity for loss-of-function mutations in MYO3A, which encodes myosin IIIA, are responsible for inherited human progressive hearing loss DFNB30. To further evaluate this hearing loss, we constructed a mouse model, Myo3a(KI/KI), that harbors the mutation equivalent to the nonsense allele responsible for the most severe human phenotype. Myo3a(KI/KI) mice were compared to their wild-type littermates. Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant. The phenotype of the Myo3a(KI/KI) mouse parallels the phenotype of human DFNB30. Hearing loss, as measured by auditory brainstem response, is reduced and progresses significantly with age. Vestibular function is normal. Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss.
Asunto(s)
Modelos Animales de Enfermedad , Pérdida Auditiva/metabolismo , Ratones , Cadenas Pesadas de Miosina/deficiencia , Miosina Tipo III/deficiencia , Factores de Edad , Animales , Secuencia de Bases , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Pérdida Auditiva/genética , Pérdida Auditiva/fisiopatología , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Cadenas Pesadas de Miosina/química , Cadenas Pesadas de Miosina/genética , Miosina Tipo III/química , Miosina Tipo III/genética , Estructura Terciaria de ProteínaRESUMEN
BACKGROUND: Moderate to severe prelingual hearing impairment (DFNB84) was observed in an extended consanguineous Palestinian kindred. All affected relatives shared a 12.5 MB homozygous haplotype on chromosome 12q21 with lod score 4.30. This homozygous region harbours the protein tyrosine phosphatase receptor Q gene PTPRQ, which is known to be essential to hearing in mouse. METHODS: Candidate genes in the 12.5 MB homozygous region were characterized genomically and sequenced in deaf and hearing relatives in the family. RESULTS: Sequence of PTPRQ in affected individuals in the extended kindred revealed c.1285C-->T, leading to p.Gln429Stop. This nonsense mutation co-segregated with hearing loss in the family and was homozygous in all affected relatives. The mutation did not appear among 288 Palestinian controls (576 chromosomes), all adults with normal hearing. No homozygous mutations in PTPRQ appeared in any of 218 other probands with hearing loss. CONCLUSION: Identification of the DFNB84 gene represents the first identification of PTPRQ mutation in human hearing loss.
Asunto(s)
Cilios/genética , Codón sin Sentido/genética , Sitios Genéticos/genética , Pérdida Auditiva/enzimología , Pérdida Auditiva/genética , Proteínas de la Membrana/genética , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Adulto , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Patrón de Herencia/genética , Masculino , Ratones , Datos de Secuencia Molecular , LinajeRESUMEN
Recessively inherited phenotypes are frequent in the Palestinian population, as the result of a historical tradition of marriages within extended kindreds, particularly in isolated villages. In order to characterise the genetics of inherited hearing loss in this population, we worked with West Bank schools for the deaf to identify children with prelingual, bilateral, severe to profound hearing loss not attributable to infection, trauma or other known environmental exposure. Of 156 families enrolled, hearing loss in 17 families (11 per cent) was due to mutations in GJB2 (connexin 26), a smaller fraction of GJB2-associated deafness than in other populations. In order to estimate how many different genes might be responsible for hearing loss in this population, we evaluated ten families for linkage to all 36 known human autosomal deafness-related genes, fully sequencing hearing-related genes at any linked sites in informative relatives. Four families harboured four novel alleles of TMPRSS3 (988DeltaA = 352stop), otoancorin (1067A > T = D356V) and pendrin (716T > A = V239D and 1001G > T = 346stop). In each family, all affected individuals were homozygous for the critical mutation. Each allele was specific to one or a few families in the cohort; none were widespread. Since epidemiological tests of association of mutations with deafness were not feasible for such rare alleles, we used functional and bioinformatics approaches to evaluate their consequences. In six other families, hearing loss was not linked to any known gene, suggesting that these families harbour novel genes responsible for this phenotype. We conclude that inherited hearing loss is highly heterogeneous in this population, with most extended families acting as genetic isolates in this context. We also conclude that the same genes are responsible for hearing loss in this population as elsewhere, so that gene discovery in these families informs the genetics of hearing loss worldwide.
Asunto(s)
Genoma Humano , Pérdida Auditiva Bilateral/genética , Árabes/genética , Niño , Mapeo Cromosómico , Conexina 26 , Conexinas/genética , Familia , Frecuencia de los Genes , Pérdida Auditiva Bilateral/epidemiología , Humanos , Israel/epidemiología , Mutación , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity. RESULTS: A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population. CONCLUSIONS: Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.
Asunto(s)
Pruebas Genéticas/métodos , Pérdida Auditiva/genética , Judíos/genética , Alelos , Animales , Árabes/genética , Proteínas Relacionadas con las Cadherinas , Cadherinas/genética , Biología Computacional , Análisis Mutacional de ADN/métodos , Exones , Proteínas de la Matriz Extracelular/genética , Efecto Fundador , Proteínas Ligadas a GPI/genética , Frecuencia de los Genes , Biblioteca de Genes , Predisposición Genética a la Enfermedad , Genética de Población , Genoma Humano , Pérdida Auditiva/epidemiología , Humanos , Mutación INDEL , Patrón de Herencia , Proteínas de la Membrana/genética , Ratones , Medio Oriente/epidemiología , Miosinas/genética , LinajeRESUMEN
In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23-p21.2/p13.3-q21.13 (DFNB83), 12q14.3-q21.2 (DFNB84; two families), 14q23.1-q31.1, and 17p12-q11.2 (DFNB85).
Asunto(s)
Estudios de Asociación Genética , Pérdida Auditiva/genética , Homocigoto , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Árabes , Mapeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 9/genética , Consanguinidad , Femenino , Humanos , Masculino , Linaje , FenotipoRESUMEN
In a large consanguineous Palestinian kindred, we previously mapped DFNB28--a locus associated with recessively inherited, prelingual, profound sensorineural hearing impairment--to chromosome 22q13.1. We report here that mutations in a novel 218-kDa isoform of TRIOBP (TRIO and filamentous actin [F-actin] binding protein) are associated with DFNB28 hearing loss in a total of nine Palestinian families. Two nonsense mutations (R347X and Q581X) truncate the protein, and a potentially deleterious missense mutation (G1019R) occurs in a conserved motif in a putative SH3-binding domain. In seven families, 27 deaf individuals are homozygous for one of the nonsense mutations; in two other families, 3 deaf individuals are compound heterozygous for the two nonsense mutations or for Q581X and G1019R. The novel long isoform of TRIOBP has a restricted expression profile, including cochlea, retina, and fetal brain, whereas the original short isoform is widely expressed. Antibodies to TRIOBP reveal expression in sensory cells of the inner ear and colocalization with F-actin along the length of the stereocilia.
Asunto(s)
Cromosomas Humanos Par 22/genética , Ligamiento Genético , Pérdida Auditiva/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Secuencia de Aminoácidos , Animales , Árabes/genética , Secuencia de Bases , Cóclea/metabolismo , Cartilla de ADN , Componentes del Gen , Humanos , Ratones , Proteínas de Microfilamentos/metabolismo , Datos de Secuencia Molecular , Linaje , Estructura Terciaria de Proteína , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADNRESUMEN
In some Palestinian communities, the prevalence of inherited prelingual deafness is among the highest in the world. As an initial step towards understanding the genetic causes of hearing loss in the Palestinian population, 48 independently ascertained probands with non-syndromic hearing loss were evaluated for mutations in the connexin 26 gene. Of the 48 deaf probands, 11 (23%) were homozygous or compound heterozygous for mutations in GJB2. Five different mutations were identified: ivs1(+1) G-->A, 35delG, 167delT, T229C, 235delC. Nine deaf probands were homozygous and only two compound heterozygous. Among 400 hearing Palestinian controls, one carrier was observed (for 167delT). We show that GJB2 ivs1(+1) G-->A disrupts splicing, yielding no detectable message. Linkage disequilibrium analysis suggests, in the Palestinian and Israeli populations, a common origin of the 35delG mutation, which is worldwide, and of 167delT, which appears specific to Israeli Ashkenazi and Palestinian populations. A high prevalence of deafness, high frequency of homozygosity rather than compound heterozygosity among deaf, and low mutation carrier frequency together reflect the high levels of consanguinity of many extended Palestinian families. Some of the 25 families with multiple cases of inherited prelingual deafness and wildtype GJB2 sequences may represent as-yet-unknown genes for inherited hearing loss.
Asunto(s)
Árabes/genética , Conexinas/genética , Sordera/congénito , Sordera/genética , Mutación , Alelos , Secuencia de Bases , Estudios de Casos y Controles , Niño , Mapeo Cromosómico , Cromosomas Humanos Par 13/genética , Conexina 26 , Consanguinidad , ADN/genética , Análisis Mutacional de ADN , Femenino , Haplotipos , Heterocigoto , Homocigoto , Humanos , Desequilibrio de Ligamiento , Masculino , Medio Oriente , Datos de Secuencia Molecular , LinajeRESUMEN
Normal vision in Drosophila requires NINAC, a class III myosin. Class III myosins are hybrid motor-signaling molecules, with an N-terminal kinase domain, highly conserved head and neck domains, and a class III-specific tail domain. In Drosophila rhabdomeres, NINAC interacts with actin filaments and with a PDZ scaffolding protein to organize the phototransduction machinery into a signaling complex. Recessive null mutations in Drosophila NINAC delay termination of the photoreceptor response and lead to progressive retinal degeneration. Here, we show that normal hearing in humans requires myosin IIIA, the human homolog of NINAC. In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA. Of 18 affected relatives in Family N, 7 are homozygous and 11 are compound heterozygous for pairs of mutant alleles. Expression of mammalian myosin IIIA is highly restricted, with the strongest expression in retina and cochlea. The involvement of homologous class III myosins in both Drosophila vision and human hearing is an evolutionary link between these sensory systems.