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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Identification of a large insertion on chromosome Xq27.1 in X-linked rec...
Identification of a large insertion on chromosome Xq27.1 in X-linked recessive HPT patients. In order to confirm the less than 28-kb deletion involving STSs b, c, and d and SNP rs732125 (Figure 1) in X-linked recessive HPT patients, PFGE restriction mapping studies (20) were undertaken. (A) The less than 28-kb deletion predicted the occurrence of an approximately 250-kb SfiI fragment in X-linked recessive HPT patients, as compared with an approximately 275-kb SfiI fragment in normal individuals, when a [32P]-labeled SOX3-derived probe for hybridization was used. (B) PFGE confirmed the presence of an approximately 275-kb SfiI fragment in normal males (open square) but revealed an unexpected larger SfiI fragment of approximately 325 kb in males affected with X-linked recessive HPT (filled square). Carrier females (circle with a dot) had both the approximately 275-kb and 325-kb SfiI fragments. The results from 3 members of family W/81 (5, 8), which consists of 48 members, are shown, and the individual’s identification code regarding generation number and position in the pedigree is as previously reported (8) to facilitate comparison between the studies. (C) These findings are consistent with the occurrence of a large, at least 75-kb [i.e., (325–275) + 28 kb] insertion at the site of the less than 28-kb deletion (del) in individuals affected with X-linked recessive HPT.