RESUMEN
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.
Asunto(s)
Envejecimiento Prematuro/genética , Secuencia de Bases , Predisposición Genética a la Enfermedad , Trastornos del Desarrollo del Lenguaje/genética , Leucoencefalopatías/genética , Eliminación de Secuencia , Tetraspaninas/genética , Edad de Inicio , Envejecimiento Prematuro/complicaciones , Envejecimiento Prematuro/etnología , Envejecimiento Prematuro/patología , Pueblo Asiatico , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , Cromosomas Humanos Par 2 , Exones , Femenino , Humanos , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Desarrollo del Lenguaje/etnología , Trastornos del Desarrollo del Lenguaje/patología , Leucoencefalopatías/complicaciones , Leucoencefalopatías/etnología , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADNRESUMEN
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.
Asunto(s)
Enfermedades Raras/genética , Enfermedades Cutáneas Genéticas/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Aldehído Oxidorreductasas/genética , Vesícula/genética , Colágeno Tipo VII/genética , Consanguinidad , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Epidermólisis Ampollosa/genética , Epidermólisis Ampollosa Distrófica/genética , Epidermólisis Ampollosa Simple/genética , Exoma , Femenino , Proteínas Filagrina , Flavoproteínas/genética , Homocigoto , Humanos , Mutación INDEL , Eritrodermia Ictiosiforme Congénita/genética , Ictiosis Vulgar/genética , Ictiosis Lamelar/genética , Proteínas de Filamentos Intermediarios/genética , Queratina-14/genética , Errores Innatos del Metabolismo Lipídico/genética , Lipooxigenasa/genética , Masculino , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Enfermedades Musculares/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linaje , Enfermedades Periodontales/genética , Fenotipo , Trastornos por Fotosensibilidad/genética , Porfiria Variegata/genética , Protoporfirinógeno-Oxidasa/genética , Síndrome de Sjögren-Larsson/genética , Factores de Transcripción/genética , Xerodermia Pigmentosa/genéticaRESUMEN
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.