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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Figure 6

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Expression of Sox3 and Casr in the developing parathyroids of mouse embr...
Expression of Sox3 and Casr in the developing parathyroids of mouse embryos. Transverse sections through the regions of the pharyngeal pouches and neck, from wild-type (normal) mouse embryos between 10.5 and 18.5 dpc, were hybridized with either Casr or Sox3 riboprobes. Casr, which is known to be expressed in the parathyroids and thyroids (6), was used as a control. (A) Casr expression was observed in the third pharyngeal pouch (Pp3) at 10.5 dpc. (B) On a serial section, Sox3 expression was observed in the posterior margins of the second (Pp2) and third pharyngeal pouch endoderm and also the foregut endoderm (Fg). (C) Sox3 and Casr (data not shown) expression were detected in the thyroid (Th) and in the thymic (Tm) and parathyroid (Pa) rudiments at 13.5 dpc. (D) Sox3 expression continued in the developing thyroid and parathyroids at 15.5 dpc. (E) However, Sox3 expression had almost ceased in the developing thyroid and parathyroids by 18.5 dpc. (F) In contrast, Casr was seen to be strongly expressed in the developing thyroid and parathyroids on a serial section at 18.5 dpc. Oe, esophagus; Tr, trachea. These results demonstrate that Sox3 is expressed, between 10.5 dpc and 15.5 dpc, in the pharyngeal pouches and developing parathyroids of the mouse embryo. Scale bars, 0.25 mm.