An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism
Michael R. Bowl, … , Michael P. Whyte, Rajesh V. Thakker
Michael R. Bowl, … , Michael P. Whyte, Rajesh V. Thakker
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2822-2831. https://doi.org/10.1172/JCI24156.
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Research Article Genetics

An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism

Abstract

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 parathyroid 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.

Authors

Michael R. Bowl, M. Andrew Nesbit, Brian Harding, Elaine Levy, Andrew Jefferson, Emanuela Volpi, Karine Rizzoti, Robin Lovell-Badge, David Schlessinger, Michael P. Whyte, Rajesh V. Thakker

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Molecular mechanism underlying the deletion-insertion abnormality involv...
Molecular mechanism underlying the deletion-insertion abnormality involving chromosomes Xq27 and 2p25 in X-linked recessive HPT. The relationships of the deletion-insertion to that of BACs (Figures 1 and 4) from chromosomes 2p25 (CTD-2029L3, RP11-1268F2, XXfos-83269E11, RP13-932E12, RP11-1294H20, and RP13-542C4) and Xq27 (RP11-51C14) are shown. DNA sequence database analyses together with a characterization of the DNA sequences of the breakpoints (Figures 2 and 3) in X-linked recessive HPT patients established that the deletion within Xq27.1 extends approximately 23–25 kb and that the insertion from chromosome 2p25.3, which inverted upon insertion, extends approximately 305–340 kb and includes exons 2–16 of the SNTG2 gene. The location of this deletion-insertion is approximately 67 kb downstream of the gene encoding SOX3, which belongs to a family of transcription factors that are involved in vertebrate embryonic development (13). For example, abnormalities of SOX3 expression are associated with developmental anomalies involving the CNS, craniofacial bones, and pituitary (15–18, 41), while abnormalities of SRY expression are associated with disorders of sexual development (49). It is likely that the deletion-insertion causes a disruption of SOX3 regulatory elements and thereby exerts a position effect on SOX3 expression.