RESUMEN
Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.
Asunto(s)
Enfermedad Coronaria/genética , Predisposición Genética a la Enfermedad , Proteínas Relacionadas con Receptor de LDL/genética , Síndrome Metabólico/genética , Mutación Missense , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Animales , Cromosomas Humanos Par 12/genética , Enfermedad Coronaria/metabolismo , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Proteínas Relacionadas con Receptor de LDL/fisiología , Lípidos/sangre , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad , Masculino , Síndrome Metabólico/metabolismo , Ratones , Persona de Mediana Edad , Células 3T3 NIH , Osteoporosis/genética , Linaje , Factores de Riesgo , Transducción de Señal , Proteínas Wnt/metabolismoRESUMEN
Patent ductus arteriosus (PDA) is a common congenital heart disease that results when the ductus arteriosus, a muscular artery, fails to remodel and close after birth. A syndromic form of this disorder, Char syndrome, is caused by mutation in TFAP2B, the gene encoding a neural crest-derived transcription factor. Established features of the syndrome are PDA, facial dysmorphology, and fifth-finger clinodactyly. Disease-causing mutations are missense and are proposed to be dominant negative. Because only a small number of families have been reported, there is limited information on the spectrum of mutations and resulting phenotypes. We report the characterization of two kindreds (K144 and K145) with Char syndrome containing 22 and 5 affected members, respectively. Genotyping revealed linkage to TFAP2B in both families. Sequencing of TFAP2B demonstrated mutations in both kindreds that were not found among control chromosomes. Both mutations altered highly conserved bases in introns required for normal splicing as demonstrated by biochemical studies in mammalian cells. The abnormal splicing results in mRNAs containing frameshift mutations that are expected to be degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency; even if produced, the protein in K144 would lack DNA binding and dimerization motifs and would likely result in haploinsufficiency. Examination of these two kindreds for phenotypes that segregate with TFAP2B mutations identified several phenotypes not previously linked to Char syndrome. These include parasomnia and dental and occipital-bone abnormalities. The striking sleep disorder in these kindreds implicates TFAP2B-dependent functions in the normal regulation of sleep.
