OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels.
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.
Huber
Celine
C
University Paris Descartes, Department of Genetics and INSERM U781, Hospital Necker Enfants-Malades, Paris, France.
Fradin
Mélanie
M
Edouard
Thomas
T
Le Merrer
Martine
M
Alanay
Yasemin
Y
Da Silva
Daniela Bezerra
DB
David
Albert
A
Hamamy
Hanan
H
van Hest
Liselotte
L
Lund
Allan M
AM
Michaud
Jacques
J
Oley
Christine
C
Patel
Chirag
C
Rajab
Anna
A
Skidmore
David L
DL
Stewart
Helen
H
Tauber
Maité
M
Munnich
Arnold
A
Cormier-Daire
Valerie
V
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
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