title: OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels.
abstract: 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.
authors.affiliation: University Paris Descartes, Department of Genetics and INSERM U781, Hospital Necker Enfants-Malades, Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Huber
authors.forename: Mélanie
authors.initials: M
authors.lastname: Fradin
authors.forename: Thomas
authors.initials: T
authors.lastname: Edouard
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Daniela Bezerra
authors.initials: DB
authors.lastname: Da Silva
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.forename: Liselotte
authors.initials: L
authors.lastname: van Hest
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.forename: Jacques
authors.initials: J
authors.lastname: Michaud
authors.forename: Christine
authors.initials: C
authors.lastname: Oley
authors.forename: Chirag
authors.initials: C
authors.lastname: Patel
authors.forename: Anna
authors.initials: A
authors.lastname: Rajab
authors.forename: David L
authors.initials: DL
authors.lastname: Skidmore
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.forename: Maité
authors.initials: M
authors.lastname: Tauber
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D005190:Family; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006130:Growth Disorders / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013577:Syndrome
chemical_list: C506299:CUL7 protein, human; D018389:Codon, Nonsense; D044842:Cullin Proteins; D003598:Cytoskeletal Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; C522000:OBSL1 protein, human; D012333:RNA, Messenger