- Research article An interstitial...

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Research article 2822 The Journal of Clinical Investigation Volume 115 Number 10 October 2005 An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3 , causes X-linked recessive hypoparathyroidism Michael R. Bowl, 1 M. Andrew Nesbit, 1 Brian Harding, 1 Elaine Levy, 2 Andrew Jefferson, 2 Emanuela Volpi, 2 Karine Rizzoti, 3 Robin Lovell-Badge, 3 David Schlessinger, 4 Michael P. Whyte, 5,6 and Rajesh V. Thakker 1 1 Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Oxford, United Kingdom. 2 Molecular Cytogenetics and Microscopy, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 3 Division of Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, United Kingdom. 4 Laboratory of Genetics, NIH, and National Institute on Aging, Baltimore, Maryland, USA. 5 Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, Missouri, USA. 6 Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri, USA. X-linked recessive hypoparathyroidism, due to parathyroid agenesis, has been mapped to a 906-kb region on Xq27 that contains 3 genes ( ATP11C , U7snRNA , and SOX3 ), and analyses have not revealed mutations. We therefore characterized this region by combined analysis of single nucleotide polymorphisms and sequence- tagged sites. This identified a 23- to 25-kb deletion, which did not contain genes. However, DNA fiber–FISH and pulsed-field gel electrophoresis revealed an approximately 340-kb insertion that replaced the deleted fragment. Use of flow-sorted X chromosome–specific libraries and DNA sequence analyses revealed that the telomeric and centromeric breakpoints on X were, respectively, approximately 67 kb downstream of SOX3 and within a repetitive sequence. Use of a monochromosomal somatic cell hybrid panel and metaphase-FISH mapping demonstrated that the insertion originated from 2p25 and contained a segment of the SNTG2 gene that lacked an open reading frame. However, the deletion-insertion [del(X)(q27.1) inv ins (X;2)(q27.1;p25.3)], which represents a novel abnormality causing hypoparathyroidism, could result in a position effect on SOX3 expression. Indeed, SOX3 expression was demonstrated, by in situ hybridization, in the developing parathy- roid tissue of mouse embryos between 10.5 and 15.5 days post coitum. Thus, our results indicate a likely new role for SOX3 in the embryonic development of the parathyroid glands. Introduction Hypoparathyroidism (HPT) is an endocrine disorder in which hypocalcemia and hyperphosphatemia are the results of a deficien- cy of parathyroid hormone (PTH) (1). The causes of HPT include trauma to the parathyroids during neck surgery, autoimmune polyendocrinopathy syndrome type 1, or the complex congential
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This note was uploaded on 05/05/2011 for the course BIOL 400 taught by Professor Dr.biology during the Spring '11 term at University of Tennessee.

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