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OBSL1 mutations in 3‐M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels
Author(s) -
Huber Celine,
Fradin Mélanie,
Edouard Thomas,
Le Merrer Martine,
Alanay Yasemin,
Da Silva Daniela Bezerra,
David Albert,
Hamamy Hanan,
van Hest Liselotte,
Lund Allan M.,
Michaud Jacques,
Oley Christine,
Patel Chirag,
Rajab Anna,
Skidmore David L.,
Stewart Helen,
Tauber Maité,
Munnich Arnold,
CormierDaire Valerie
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21150
Subject(s) - biology , genetics , missense mutation , locus (genetics) , gene , candidate gene , nonsense mediated decay , gene expression , microarray analysis techniques , microarray , microbiology and biotechnology , mutation , rna , rna splicing
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. Hum Mutat 30:1–7, 2009. © 2009 Wiley‐Liss, Inc.