Assuntos
Povo Asiático/genética , Desmogleína 1/genética , Heterozigoto , Ceratodermia Palmar e Plantar Difusa/diagnóstico , Ceratodermia Palmar e Plantar Difusa/genética , Mutação de Sentido Incorreto/genética , Feminino , Pé/patologia , Mãos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 × 10-9, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 × 10-18, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis.
Assuntos
Povo Asiático/genética , Etnicidade/genética , Predisposição Genética para Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hanseníase/genética , Mutação de Sentido Incorreto/genética , Proteínas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Fatores de Risco , Transativadores/genética , Regulação para Cima/genética , Sequenciamento do Exoma , Adulto JovemAssuntos
Artrite/diagnóstico , Artrite/genética , Povo Asiático/genética , Mutação de Sentido Incorreto/genética , Proteína Adaptadora de Sinalização NOD2/genética , Sinovite/diagnóstico , Sinovite/genética , Uveíte/diagnóstico , Uveíte/genética , Criança , Humanos , Masculino , Sarcoidose/diagnóstico , Sarcoidose/genéticaAssuntos
Canal Anal/patologia , Povo Asiático/genética , ATPases Transportadoras de Cálcio/genética , Genitália Feminina/patologia , Mutação de Sentido Incorreto/genética , Pênfigo Familiar Benigno/genética , Adulto , Feminino , Humanos , Pênfigo Familiar Benigno/diagnóstico , Dermatopatias/diagnóstico , Dermatopatias/genéticaAssuntos
Adenosina Desaminase/genética , Povo Asiático/genética , Mutação de Sentido Incorreto/genética , Transtornos da Pigmentação/congênito , Proteínas de Ligação a RNA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genéticaRESUMO
OBJECTIVE: The pathologic basis of systemic juvenile idiopathic arthritis (JIA) is a subject of some controversy, with evidence for both autoimmune and autoinflammatory etiologies. Several monogenic autoinflammatory disorders have been described, but thus far, systemic JIA has only been attributed to a mutation of MEFV in rare cases and has been weakly associated with the HLA class II locus. This study was undertaken to identify the cause of an autosomal-recessive form of systemic JIA. METHODS: We studied 13 patients with systemic JIA from 5 consanguineous families, all from the southern region of Saudi Arabia. We used linkage analysis, homozygosity mapping, and whole-exome sequencing to identify the disease-associated gene and mutation. RESULTS: Linkage analysis localized systemic JIA to a region on chromosome 13 with a maximum logarithm of odds score of 11.33, representing the strongest linkage identified to date for this disorder. Homozygosity mapping reduced the critical interval to a 1.02-Mb region defined proximally by rs9533338 and distally by rs9595049. Whole-exome sequencing identified a homoallelic missense mutation in LACC1, which encodes the enzyme laccase (multicopper oxidoreductase) domain-containing 1. The mutation was confirmed by Sanger sequencing and segregated with disease in all 5 families based on an autosomal-recessive pattern of inheritance and complete penetrance. CONCLUSION: Our findings provide strong genetic evidence of an association of a mutation in LACC1 with systemic JIA in the families studied. Association of LACC1 with Crohn's disease and leprosy has been reported and justifies investigation of its role in autoinflammatory disorders.
Assuntos
Artrite Juvenil/genética , Ligação Genética/genética , Lacase/genética , Mutação de Sentido Incorreto/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Exoma/genética , Feminino , Homozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Arábia Saudita , Adulto JovemAssuntos
Mutação de Sentido Incorreto/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Povo Asiático , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Adulto JovemRESUMO
Molecular detection was compared with the mouse footpad inoculation test for detection of dapsone resistance in 38 strains of Mycobacterium leprae. Mutations of the folP1 gene (at codons 53 or 55) were found in 6 of 6 strains with high-level resistance, in 3 of 4 strains with intermediate-level resistance, and in 1 of 6 strains with low-level resistance, but not in 22 dapsone-susceptible strains. In cases of infection with strains of M. leprae carrying the folP1 mutation, therapy with dapsone may be replaced by therapy with a fluoroquinolone.