RESUMEN
Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes, including SOD1, NEK1, TARDBP, and FUS While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Análisis Mutacional de ADN/métodos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Femenino , Variación Genética , Humanos , Masculino , Mutación , Quinasa 1 Relacionada con NIMA/genética , Dominios Proteicos/genética , Proteína FUS de Unión a ARN/genética , Factores de Riesgo , Superóxido Dismutasa-1/genética , Población Blanca/genética , Secuenciación del Exoma/métodosRESUMEN
Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.
Asunto(s)
Catarata/genética , Disfunción Cognitiva/genética , Distrofia Muscular de Cinturas/genética , Anomalías Musculoesqueléticas/genética , Monoéster Fosfórico Hidrolasas/genética , Adolescente , Adulto , Alelos , Animales , Encéfalo/patología , Niño , Preescolar , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Mutación , Linaje , Adulto Joven , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
Ultra-rare biallelic pathogenic variants in geranylgeranyl diphosphate synthase 1 (GGPS1) have recently been associated with muscular dystrophy/hearing loss/ovarian insufficiency syndrome. Here, we describe 11 affected individuals from four unpublished families with ultra-rare missense variants in GGPS1 and provide follow-up details from a previously reported family. Our cohort replicated most of the previously described clinical features of GGPS1 deficiency; however, hearing loss was present in only 46% of the individuals. This report consolidates the disease-causing role of biallelic variants in GGPS1 and demonstrates that hearing loss and ovarian insufficiency might be a variable feature of the GGPS1-associated muscular dystrophy.