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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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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Figure 3

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Characterization of the deletion-insertion in X-linked recessive HPT. (A...
Characterization of the deletion-insertion in X-linked recessive HPT. (A) The DNA sequences of the centromeric and telomeric breakpoints (Point-cen and Point-tel, respectively) were determined using genomic libraries generated from EBV-lymphoblastoid DNA and flow-sorted X chromosomes of an affected male (22). The DNA sequence from the centromeric boundary consisted of a dinucleotide repeat, and the DNA sequence from the telomeric boundary was therefore used to design ISPs (ISP1, ISP2, and ISP3) and XSPs (XSPF and XSPR) for the further characterization of the insertion. The sizes of the PCR products obtained with each primer pair are indicated. The locations of STSs a–e (Figure 1) are shown. (B) Use of primers ISP1 and ISP2 and DNA from a monochromosomal somatic cell hybrid panel revealed that the insert sequence originated from chromosome 2. 1+X, DNA from cell with chromosomes 1 and X; Hs, human DNA; Mm, mouse DNA; Ha, hamster DNA; –, no DNA. (C) Use of primers ISP3 and XSPR, which flank the telomeric breakpoint, identified the deletion-insertion in affected males (filled squares) and carrier females (circles with a dot). Use of primers XSPF and XSPR identified the normal X chromosome allele in unaffected males (open squares), unaffected females (open circles), and carrier females. The results from 8 members of family W/81 are shown, and the identification code used for individuals is as described in Figure 2. Individual 7a, who is an unaffected sister, has not been reported in previous studies (8). The combined results from all the members of families W/81(8) and P/60 (8) yielded a LOD score of 8.1 at 0% recombination.