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The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1 |
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| Authors: | Dan Hanson Philip G Murray Amit Sud Samia A Temtamy Andrea Superti-Furga Jill Urquhart Emma Hilton Peter Scambler Peter E Clayton |
| Institution: | 1 Endocrine Sciences, Faculty of Medical & Human Sciences, University of Manchester, Manchester M13 9NT, UK 2 Medical Genetics, Faculty of Medical & Human Sciences, University of Manchester, Manchester M13 9PT, UK 3 Central Manchester University Hospitals Foundation Trust, Manchester M13 OJH, UK 4 Department of Clinical Genetics, Division of Human Genetics & Human Genome Research, National Research Centre, 12311 Cairo, Egypt 5 Centre for Pediatrics & Adolescent Medicine, University of Freiburg, 79106 Freiburg, Germany 6 North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow HA1 3UJ, UK 7 Molecular Medicine Unit, Institute of Child Health, London WC1N 1EH, UK |
| Abstract: | 3-M syndrome is an autosomal-recessive primordial growth disorder characterized by significant intrauterine and postnatal growth restriction. Mutations in the CUL7 gene are known to cause 3-M syndrome. In 3-M syndrome patients that do not carry CUL7 mutations, we performed high-density genome-wide SNP mapping to identify a second locus at 2q35-q36.1. Further haplotype analysis revealed a 1.29 Mb interval in which the underlying gene is located and we subsequently discovered seven distinct null mutations from 10 families within the gene OBSL1. OBSL1 is a putative cytoskeletal adaptor protein that localizes to the nuclear envelope. We were also able to demonstrate that loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels and suggesting that both proteins are involved within the same molecular pathway. |
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