RESUMO
BACKGROUND: Mutations in MPZL2, the characteristic genetic etiology of autosomal recessive deafness loci 111 (DFNB111), cause non-syndromic and moderate sensorineural hearing loss. METHODS: In this study, we analyzed the phenotype and genotype of eight pedigrees consisting of 10 hearing loss patients with bi-allelic pathogenic or likely pathogenic variants in MPZL2. These patients were identified from a 3272 Chinese patient cohort who underwent genetic testing. RESULTS: Apart from symmetrical and moderate sensorineural hearing loss, the MPZL2-related phenotype was characterized by progressive hearing loss with variation in the onset age (congenital defect to onset at the young adult stage). We determined that in the Chinese population, the genetic load of MPZL2 defects was 0.24% (8/3272) in patients diagnosed with hearing loss and 7.02% (8/114) in patients diagnosed with hereditary moderate sensorineural hearing loss caused by STRC, OTOA, OTOG, OTOGL, TECTA, MPZL2 and others. Three known MPZL2 variants (c.220C > T (p.Gln74*), c.68delC (p.Pro23Leufs*2), c.463delG (p.Ala155Leufs*10)) and a novel start loss variant (c.3G > T (p.Met1?)) were identified. MPZL2 c.220C > T was identified as the hotspot variant in the Chinese population and even in East Asia compared with c.72delA (p.Ile24Metfs*22) in European and West Asia through allele frequency. CONCLUSIONS: We concluded that apart from moderate HL, progressive HL is another character of MPZL2-related HL. No specified variant was verified for the progression of HL, the penetrance and expressivity cannot be determined yet. A novel MPZL2 variant at the start codon was identified, enriching the variant spectrum of MPZL2. The hotspot variants of MPZL2 vary in different ethnicities. This study provides valuable data for the diagnosis, prognosis evaluation and genetic counseling of patients with moderate sensorineural hearing loss related to MPZL2.
Assuntos
Surdez , Perda Auditiva Neurossensorial , Humanos , Adulto Jovem , Povo Asiático/genética , Moléculas de Adesão Celular , China , Surdez/etnologia , Surdez/genética , Perda Auditiva Neurossensorial/etnologia , Perda Auditiva Neurossensorial/genética , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de MembranaRESUMO
Abstract Introduction: In different parts of the world, mutations in the GJB2 gene are associated with nonsyndromic hearing loss, and the homozygous 35delG mutation (p.Gly12Valfs*2) is a major cause of hereditary hearing loss. However, the 35delG mutation is not equally prevalent across ethnicities, making it important to study other mutations, especially in multiethnic countries such as Brazil. Objective: This study aimed to identify different mutations in the GJB2 gene in patients with severe to profound nonsyndromic sensorineural hearing loss of putative genetic origin, and who were negative or heterozygote for the 35delG mutation. Methods: Observational study that analyzed 100 ethnically characterized Brazilian patients with nonsyndromic severe to profound sensorineural hearing loss, who were negative or heterozygote for the 35delG mutation. GJB2 mutations were detected by DNA-based sequencing in this population. Participants' ethnicities were identified as Latin European, Non-Latin European, Jewish, Native, Turkish, Afro-American, Asian and Others. Results: Sixteen participants were heterozygote for the 35delG mutation; 14 participants, including three 35delG heterozygote's, had nine different alterations in the GJB2 gene. One variant, p.Ser199Glnfs*9, detected in two participants, was previously unreported. Three variants were pathogenic (p.Trp172*, p.Val167Met, and p.Arg75Trp), two were non-pathogenic (p.Val27Ile and p.Ile196Thr), and three variants were indeterminate (p.Met34Thr, p.Arg127Leu, and p.Lys168Arg). Three cases of compound heterozygosity were detected: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], and p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). Conclusion: This study detected previously unclassified variants and one case of previously unreported compound heterozygosity.
Resumo Introdução: Em diferentes partes do mundo, mutações do gene GJB2 estão associadas a perda auditiva não sindrômica e a mutação homozigótica 35delG (p.Gly12Valfs*2) é uma das principais causas de perda auditiva hereditária. No entanto, a mutação 35delG não é igualmente prevalente em todas as etnias, faz com que seja importante estudar outras mutações, especialmente em países multiétnicos, como o Brasil. Objetivo: Identificar diferentes mutações no gene GJB2 em pacientes com perda auditiva neurossensorial grave ou profunda não sindrômica de origem genética putativa e negativos ou heterozigotos para a mutação 35delG. Método: Estudo observacional que analisou 100 pacientes brasileiros caracterizados etnicamente, com perda auditiva neurossensorial grave ou profunda não sindrômica, negativos ou heterozigotos para a mutação 35delG. As mutações de GJB2 foram detectadas por sequenciamento baseado no DNA nessa população. As etnias dos participantes foram identificadas como latino-europeia, não latino-europeia, judaica, nativa, turca, negra, asiática e outras. Resultados: Dezesseis participantes eram heterozigotos para a mutação 35delG e 14, incluindo três heterozigotos para 35delG, apresentaram nove alterações no gene GJB2. Uma variante, p.Ser199Glnfs*9, detectada em dois participantes, não havia sido relatada anteriormente. Três variantes eram patogênicas (p.Trp172*, p.Val167Met, e p.Arg75Trp), duas não patogênicas (p.Val27Ile e p.Ile196Thr) e três indeterminadas (p.Met34Thr, p.Arg127Leu, e p.Lys168Arg). Três casos de heterozigosidade composta foram detectados: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], e p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). Conclusão: Este estudo detectou variantes não classificadas anteriormente e um caso de heterozigosidade composta ainda não relatada.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Conexinas/genética , Perda Auditiva Neurossensorial/etnologia , Perda Auditiva Neurossensorial/genética , Mutação , Índice de Gravidade de Doença , Brasil/etnologia , Surdez/etnologia , Surdez/genética , Frequência do Gene , Perda Auditiva Neurossensorial/congênitoRESUMO
Abstract Introduction: There is inconclusive evidence whether osteoporosis increases risk of hearing loss in current literature. Objective: We conducted this meta-analysis to determine whether there is an association between hearing loss and osteoporosis. Methods: This systematic review and meta-analysis was conducted from studies of MEDLINE, EMBASE, and LILACS. Osteoporosis was defined as having a bone mineral density with a T-score of less than −2.5 standard deviation. The outcome was hearing loss as assessed by audiometry or self-reported assessment. Random-effects model and pooled hazard ratio, risk ratio, or odds ratio of hearing loss with 95% confidence intervals were compared between normal bone mineral density and low bone mineral density or osteoporosis. Results: A total of 16 articles underwent full-length review. Overall, there was a statistically significant increased odds of hearing loss in the low bone mineral density or osteoporosis group with odds ratio of 1.20 (95% confidence intervals 1.01-1.42, p = 0.04, I 2 = 82%, Pheterogeneity = 0.01). However, the study from Helzner et al. reported significantly increase odds of hearing loss in the low bone mineral density in particular area and population included femoral neck of black men 1.37 (95% confidence intervals 1.07-1.76, p = 0.01) and total hip of black men 1.36 (95% confidence intervals 1.05-1.76, p = 0.02). Conclusion: Our study proposed the first meta-analysis that demonstrated a probable association between hearing loss and bone mineral density. Osteoporosis could be a risk factor in hearing loss and might play an important role in age-related hearing loss.
Abstract Introduction: There is inconclusive evidence whether osteoporosis increases risk of hearing loss in current literature. Objective: We conducted this meta-analysis to determine whether there is an association between hearing loss and osteoporosis. Methods: This systematic review and meta-analysis was conducted from studies of MEDLINE, EMBASE, and LILACS. Osteoporosis was defined as having a bone mineral density with a T-score of less than −2.5 standard deviation. The outcome was hearing loss as assessed by audiometry or self-reported assessment. Random-effects model and pooled hazard ratio, risk ratio, or odds ratio of hearing loss with 95% confidence intervals were compared between normal bone mineral density and low bone mineral density or osteoporosis. Results: A total of 16 articles underwent full-length review. Overall, there was a statistically significant increased odds of hearing loss in the low bone mineral density or osteoporosis group with odds ratio of 1.20 (95% confidence intervals 1.01-1.42, p = 0.04, I 2 = 82%, Pheterogeneity = 0.01). However, the study from Helzner et al. reported significantly increase odds of hearing loss in the low bone mineral density in particular area and population included femoral neck of black men 1.37 (95% confidence intervals 1.07-1.76, p = 0.01) and total hip of black men 1.36 (95% confidence intervals 1.05-1.76, p = 0.02). Conclusion: Our study proposed the first meta-analysis that demonstrated a probable association between hearing loss and bone mineral density. Osteoporosis could be a risk factor in hearing loss and might play an important role in age-related hearing loss.
Assuntos
Humanos , Masculino , Feminino , Osteoporose/complicações , Perda Auditiva Condutiva-Neurossensorial Mista/etiologia , Perda Auditiva Condutiva/etiologia , Perda Auditiva Neurossensorial/etiologia , Osteoporose/etiologia , Densidade Óssea/fisiologia , Fatores Sexuais , Fatores de Risco , Fatores Etários , Perda Auditiva Condutiva-Neurossensorial Mista/etnologia , Perda Auditiva Condutiva/etnologia , Perda Auditiva Neurossensorial/etnologiaRESUMO
The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive. Rev. Biol. Trop. 62 (4): 1285-1293. Epub 2014 December 01.
La mutación p.thr124Met en la proteína mielina cero (MPZ) causa la enfermedad de Charcot-Marie-Tooth tipo 2J, una neuropatía periférica con síntomas adicionales como alteraciones pupilares y sordera. Se ha observado en varias familias alrededor del mundo, originarias de Alemania, Bélgica, Japón, Italia y Norteamérica, entre otras. Aquí reportamos a pacientes centroamericanos provenientes de Costa Rica que acarrean esta mutación. Se realizaron análisis clínico, electrofisiológico y molecular de pacientes y controles, incluyendo secuenciación del gen y de marcadores ligados a éste. Estos pacientes comparten casi por completo el haplotipo con dos pacientes belgas no emparentados. Como resultado del análisis de los haplotipos, basado en diez marcadores (siete SNPs, dos microsatélites y un elemento poli-A intrónico), se sugiere que se ha dado un efecto fundador en la migración de este alelo.