The Journal of Clinical Investigation
An interstitial deletion-insertion involving
chromosomes 2p25.3 and Xq27.1, near
causes X-linked recessive hypoparathyroidism
Michael R. Bowl,
M. Andrew Nesbit,
Michael P. Whyte,
and Rajesh V. Thakker
Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes,
Endocrinology and Metabolism (OCDEM), Churchill Hospital, Oxford, United Kingdom.
Molecular Cytogenetics and Microscopy,
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Division of Developmental Genetics,
Medical Research Council (MRC) National Institute for Medical Research, London, United Kingdom.
Laboratory of Genetics, NIH, and
National Institute on Aging, Baltimore, Maryland, USA.
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children,
St. Louis, Missouri, USA.
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 (
), 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
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
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
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
in the embryonic development of the parathyroid glands.
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