RESUMO
BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.
Assuntos
Doenças Raras/genética , Dermatopatias Genéticas/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Aldeído Oxirredutases/genética , Vesícula/genética , Colágeno Tipo VII/genética , Consanguinidade , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Simples/genética , Exoma , Feminino , Proteínas Filagrinas , Flavoproteínas/genética , Homozigoto , Humanos , Mutação INDEL , Eritrodermia Ictiosiforme Congênita/genética , Ictiose Vulgar/genética , Ictiose Lamelar/genética , Proteínas de Filamentos Intermediários/genética , Queratina-14/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipoxigenase/genética , Masculino , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linhagem , Doenças Periodontais/genética , Fenótipo , Transtornos de Fotossensibilidade/genética , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genética , Síndrome de Sjogren-Larsson/genética , Fatores de Transcrição/genética , Xeroderma Pigmentoso/genéticaRESUMO
Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.
Assuntos
Artrite/genética , Doenças Autoimunes/genética , Proteína Coatomer/genética , Complexo de Golgi/metabolismo , Doenças Pulmonares Intersticiais/genética , Sequência de Aminoácidos , Pré-Escolar , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Lactente , Escore Lod , Masculino , Dados de Sequência Molecular , Linhagem , Transporte ProteicoRESUMO
White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
