Pseudohypoparathyroidism (PHP) type 1 is an autosomal dominant disorder characterized by biochemical hypoparathyroidism due to resistance of target tissues to parathyroid hormone (PTH). Two fundamentally different forms of PHP type 1 have been described. In PHP type 1a, mutations in the GNAS1 gene lead to reduced expression or activity of the alpha subunit of the G protein (Gs alpha) that couples heptahelical receptors for PTH and many other hormones to activation of adenylyl cyclase. Accordingly, widespread deficiency of Gs alpha is associated with resistance not only to PTH but also to other hormones that act by stimulating adenylyl cyclase. By contrast, Gs alpha is normal in PHP type 1b, and hormone resistance is limited to PTH target tissues. These observations had suggested that the defect in PHP type 1b was the type 1 PTH receptor, but molecular analysis of this gene has not revealed mutations. The goal of this project is to identify and characterize the gene for PHP type 1b. We have used linkage analysis to assign the locus for PHP type 1b (designated PHP1b) to 10q26. This region contains a candidate gene that encodes the type 5 G protein-coupled receptor kinase (GRK 5), a protein kinase that can phosphorylate and desensitize the type 1 PTH receptor. To determine the PHP1b gene, a positional cloning strategy will be used involving the following approaches: (1) Further refine the PHP1b locus first by haplotype analysis of three additional PHP type 1b families we have ascertained, and subsequently by further analysis of all families using additional polymorphic markers mapped to this region. (2) Screen publicly available YAC clones and assemble a linear contig spanning the locus, and increase the resolution of the physical map. (3) Identify coding sequences in this region by review of publicly available EST maps, screening cDNA libraries by GeneTrapper methodology, and by exon-trapping. (4) Characterize transcripts through evaluation of homology to other known genes, patterns of tissue-specific expression, and cross-species conservation. (5) Perform mutational analysis of genomic DNA samples from familial and sporadic cases. Once the PHP1b gene is identified, the long-range goal will be to characterize the function of the gene product, to examine genotype-phenotype correlations, and to understand its role in regulating expression or action of the PTH receptor in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK056178-04S1
Application #
6658908
Study Section
General Medicine B Study Section (GMB)
Program Officer
Tondravi, Mehrdad M
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$114,579
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sanchez, Janine; Perera, Erasmo; Jan de Beur, Suzanne et al. (2011) Madelung-like deformity in pseudohypoparathyroidism type 1b. J Clin Endocrinol Metab 96:E1507-11
Lietman, Steven A; Germain-Lee, Emily L; Levine, Michael A (2010) Hypercalcemia in children and adolescents. Curr Opin Pediatr 22:508-15
Lietman, Steven A; Yin, Lihong; Levine, Michael A (2010) SH3BP2 mutations potentiate osteoclastogenesis via PLC?. J Orthop Res 28:1425-30
Crane, Janet L; Shamblott, Michael J; Axelman, Joyce et al. (2009) Imprinting status of Galpha(s), NESP55, and XLalphas in cell cultures derived from human embryonic germ cells: GNAS imprinting in human embryonic germ cells. Clin Transl Sci 2:355-60
Lietman, Steven A; Yin, Lihong; Levine, Michael A (2008) SH3BP2 is an activator of NFAT activity and osteoclastogenesis. Biochem Biophys Res Commun 371:644-8
Lietman, Steven A; Goldfarb, James; Desai, Nina et al. (2008) Preimplantation genetic diagnosis for severe albright hereditary osteodystrophy. J Clin Endocrinol Metab 93:901-4
Germain-Lee, Emily L (2006) Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type 1a. Pediatr Endocrinol Rev 3 Suppl 2:318-27
Lietman, Steven A; Ding, Changlin; Levine, Michael A (2005) A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia. J Bone Joint Surg Am 87:2489-94
Germain-Lee, Emily L; Schwindinger, William; Crane, Janet L et al. (2005) A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 146:4697-709
Lietman, Steven A; Ding, Changlin; Cooke, David W et al. (2005) Reduction in Gsalpha induces osteogenic differentiation in human mesenchymal stem cells. Clin Orthop Relat Res :231-8

Showing the most recent 10 out of 13 publications