OBSL1 mutations in 3‐M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels |
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Authors: | Celine Huber Mélanie Fradin Thomas Edouard Martine Le Merrer Yasemin Alanay Daniela Bezerra Da Silva Albert David Hanan Hamamy Liselotte van Hest Allan M. Lund Jacques Michaud Christine Oley Chirag Patel Anna Rajab David L. Skidmore Helen Stewart Maité Tauber Arnold Munnich Valerie Cormier‐Daire |
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Affiliation: | 1. University Paris Descartes, Department of Genetics and INSERM U781, Hospital Necker Enfants‐Malades, Paris, France;2. Pediatric Endocrinology Service, Hospital Purpan, Toulouse, France;3. Department of Pediatrics, Ishan Dogramaci Children's Hospital, Ankara, Turkey;4. Genetic Service and Pediatric Department, CHU Sainte Justine, Montreal, Quebec, Canada;5. Clinical Genetics Unit, Nantes Hospital, Nantes, France;6. National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan;7. VU University Medical Center, Amsterdam, The Netherlands;8. Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark;9. Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, United Kingdom;10. Royal Hospital, Muscat, Sultanate of Oman;11. Maritime Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada;12. Department of Clinical Genetics, Churchill Hospital, Oxford, United Kingdom |
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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. Hum Mutat 30:1–7, 2009. © 2009 Wiley‐Liss, Inc. |
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Keywords: | 3‐M syndrome OBSL1 growth retardation IGFBP2 IGFBP5 |
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