RESUMEN
3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35-36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins.
Asunto(s)
Codón sin Sentido/genética , Proteínas del Citoesqueleto/genética , Regulación de la Expresión Génica , Trastornos del Crecimiento/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Mutación Missense/genética , Adulto , Células Cultivadas , Niño , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Proteínas del Citoesqueleto/metabolismo , Familia , Femenino , Fibroblastos , Trastornos del Crecimiento/etnología , Trastornos del Crecimiento/metabolismo , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , SíndromeRESUMEN
The 3M syndrome is a rare autosomal recessive disorder recently ascribed to mutations in the CUL7 gene and characterized by severe pre- and postnatal growth retardation. Studying a series of 33 novel cases of 3M syndrome, we have identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations and one paternal isodisomy of chromosome 6 encompassing a CUL7 mutation. Lack of mutations in 10/33 cases and exclusion of the CUL7 locus on chromosome 6p21.1 in six consanguineous families strongly support the genetic heterogeneity of the 3M syndrome.