Nature Genetics
37, 1119 - 1124 (2005)
Published online: 4 September 2005; | doi:10.1038/ng1628
Identification of mutations in CUL7 in 3-M syndromeCéline Huber1, 15, Dora Dias-Santagata2, 15, Anna Glaser3, James O'Sullivan4, Raja Brauner5, Kenneth Wu2, Xinsong Xu2, Kerra Pearce3, Rong Wang6, Maria Luisa Giovannucci Uzielli7, Nathalie Dagoneau1, Wassim Chemaitilly1, Andrea Superti-Furga8, Heloisa Dos Santos9, André Mégarbané10, Gilles Morin11, Gabriele Gillessen-Kaesbach12, Raoul Hennekam3, Ineke Van der Burgt13, Graeme C M Black4, Peter E Clayton14, Andrew Read4, Martine Le Merrer1, Peter J Scambler3, Arnold Munnich1, Zhen-Qiang Pan2, Robin Winter3
& Valérie Cormier-Daire11
Université Paris-Descartes, Faculté de Médecine, INSERM, AP-HP, Hôpital Necker Enfants Malades, U393 and Department of Medical Genetics, 149 rue de Sèvres 75015, Paris, France. 2
Department of Oncological Sciences, The Mount Sinai School of Medicine, New York, New York, USA. 3
Genes, Development and Disease Theme, Institute of Child Health, London WC1N 1EH, UK. 4
Department of Clinical Genetics, Central Manchester and Manchester Children's, University Hospitals NHS Trust, St. Mary's Hospital, Manchester, M13 0JH, UK. 5
Pediatric Endocrinology Unit, CHU Bicêtre, 94275 Le Kremlin Bicêtre, France. 6
Department of Human Genetics, The Mount Sinai School of Medicine, New York, New York 10029-6574, USA. 7
Genetics and Molecular Medicine Unit, Department of Paediatrics, University of Florence, Florence, Italy. 8
Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. 9
Medical Genetics Service, Hospital Sta. Maria, Lisboa, Portugal. 10
Unité de Génétique Médicale, Université Saint Joseph, Beirut, Lebanon. 11
Clinical Genetics Unit, Department of Paediatrics, Amiens University Hospital, Amiens, France. 12
Institut für Humangenetik, Universität Essen, 55 D-45122 Essen, Germany. 13
University Medical Center Nijmegen, Department of Human Genetics 417, 6525GA Nijmegen, The Netherlands. 14
Endocrine Science Research Group, University of Manchester, Manchester M13 9PT, UK. 15
These authors contributed equally to this work.
Correspondence should be addressed to Valérie Cormier-Daire cormier@necker.fr Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion1. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M−associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.
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