This research project will investigate the molecular basis of pseudohypoparathyroidism (PHP) type 1a. This inherited disorder is characterized by widespread endocrine dysfunction compatible with decreased hormone responsiveness of adenylate cyclase in diverse tissues, due to deficient activity of the alpha subunit of the stimulatory guanine nucleotide-binding regulatory protein (Gs) of adenylate cyclase. Gs functions as a transmembrane signaling molecule and transducer of hormone action by stimulating adenylate cyclase catalytic activity in response to occupancy of tissue- specific receptors by hormones. Cultured fibroblasts from most patients with PHP type 1a have reduced levels of Gs alpha mRNA; in contrast, cultured fibroblasts from other PHP type 1a patients have normal levels of Gs alpha mRNA. The central importance of Gs to the regulation of hormone-responsive adenylate cyclase in general, and to the understanding of the basis for PHP type 1a in particular, encourages investigation of the potential molecular defects that may alter structure and function of this protein. To study the molecular basis for deficiency of Gs in PHP type 1a we will: 1) Use Gs alpha cDNA probes to perform restriction endonuclease analysis of normal and suspected defective Gs alpha genes. These studies may permit direct determination of structural defect(s) in the Gs alpha gene in patients with PHP type 1a. In addition, identification of restriction fragments length polymorphisms in the Gs alpha gene will enable us to determine by linkage analysis whether inheritance of Gs alpha deficiency co- segregates with inheritance of a specific (and possibly mutant) Gs alpha gene. 2) Determine whether decreased transcriptional activity of the Gs alpha gene or whether post-transcriptional defects in processing, stability, or translation of fibroblast Gs alpha mRNA cause Gs alpha deficiency in patients with either reduced or normal levels of Gs alpha mRNA. 3) Determine the chromosomal localization and the sequence of the normal Gs alpha gene and to clone and sequence abnormal Gs alpha genes. These studies will identify directly the mutations that cause Gs alpha deficiency. Elucidation of molecular defects in the gene or Gs alpha will provide important insights into the organization, structure and function of the Gs alpha gene and may identify new mechanisms of gene dysfunction. Moreover, description of the molecular defects leading to Gs alpha deficiency will form the basis for rational design of specific tests for prenatal diagnosis of particular forms of PHP type 1a.
| 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 |
| 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 |
| Jan de Beur, Suzanne; Ding, Changlin; Germain-Lee, Emily et al. (2003) Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet 73:314-22 |
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