RESUMEN
We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).
Asunto(s)
Angiopoyetinas/genética , Codón sin Sentido , Hipobetalipoproteinemias/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , HDL-Colesterol/sangre , HDL-Colesterol/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , Análisis Mutacional de ADN , Femenino , Ligamiento Genético , Humanos , Masculino , LinajeRESUMEN
BACKGROUND: Dilated cardiomyopathy (DCM), which is characterized by left ventricular enlargement and systolic dysfunction, is divided into cases with a clear predisposing condition (eg, hypothyroidism, chemotherapeutic agents, alcoholism, ischemia) and those of unknown cause (idiopathic DCM). Many cases (20%-35%) of DCM are familial, implicating a genetic contribution to the etiology. More than 30 genes have been identified, many involving "private" mutations not shared among families. Evidence suggests that nonfamilial cases also have a genetic predisposition, again involving many genes. The goal of this study was to identify mutations in genes associated with DCM in a Québec study sample including familial and nonfamilial DCM cases. HYPOTHESIS: A prioritized gene study conducted within a framework for the classification of identified genetic variants could yield etiological information even in the absence of family data. METHODS: We sequenced 4 previously identified genes: lamin A/C (LMNA), cardiac troponin T type 2 (TNNT2), titin-cap (TCAP), and phospholamban (PLN). RESULTS: We discovered a nonsense mutation in the LMNA gene and a frameshift mutation in the TNNT2 gene, as well as other clinically significant variants that were not observed in publicly available databases or in Québec-based controls. PLN was sequenced to investigate a previously published promoter variant. However, our data confirm that this variant does not have a causal role in DCM. CONCLUSIONS: Despite high locus and allele heterogeneity, we demonstrate that a prioritized gene study, combined with next-generation exome-sequencing data, can be fruitful for the identification of DCM mutations.
Asunto(s)
Proteínas de Unión al Calcio/genética , Cardiomiopatía Dilatada/genética , Codón sin Sentido , Conectina/genética , Mutación del Sistema de Lectura , Lamina Tipo A/genética , Troponina T/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Análisis Mutacional de ADN , Exoma , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , QuebecRESUMEN
Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.