U.S. Department of Health and Human Services

Metabolic Diseases Branch

Lee S. Weinstein, M.D., Chief


Endocrine Signaling and Oncogenesis Section

William F. Simonds, M.D.

The Endocrine Signaling and Oncogenesis Section studies the genetics and pathogenesis of familial forms of hyperparathyroidism and parathyroid cancer. This work includes work on the biology of CDC73/HRPT2, a tumor suppressor gene whose inactivation has been implicated in parathyroid malignancy. In addition, the Section is studying the biology of a unique brain and endocrine tissue-specific G protein complex (GΒ5-R7 RGS). These studies may have important implications for our basic understanding of neoplasia and neuroendocrine signaling. Specific projects investigate the pathogenesis and clinical spectrum of familial isolated hyperparathyroidism (FIHP), parathyroid cancer, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). Approximately 15 percent of all affected by HPT-JT have parathyroid cancer, and nearly 10 percent of adult cases appear to be silent carriers. The trait links to the CDC73/HRPT2 locus at 1q25-q31. CDC73/HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and parathyroid cancer.

Research in this Section also focuses on the G protein β5 complex, with regulator of G protein signaling (RGS) proteins. G protein β5 is a neuronally expressed, structurally divergent G protein β isoform which may be functionally specialized. In general, RGS proteins act as GTPase activating proteins targeting Gα subunits and thus can help turn off G protein signaling. Recent evidence suggests, however, that certain RGS proteins can also function as signal transducers or effectors in their own right. G β5 forms a tight complex with RGS proteins of the R7 subclass in brain. Such complexes are expressed in the cell nucleus and cytoplasm (in addition to the plasma membrane). These observations are unexplained by current models of RGS. Researchers in the Section are investigating the function of the highly conserved Gβ5/ R7 RGS protein heterodimers in brain and neuroendocrine cells.

Signal Transduction Section

Lee S. Weinstein, M.D.

The Signal Transduction Section studies the genetics and pathogenesis of parathyroid hormone resistance disorders that are caused by genetic defects of a G protein involved in hormone signaling. These include pseudohypoparathyroidism and Albright hereditary osteodystrophy (AHO). Researchers use the human genetic model of AHO, which is associated with heterozygous inactivating mutations in the Gs α-subunit gene (GNAS) and a mouse model with heterozygous inactivation of Gnas. Research in the Section has demonstrated that Gsα is imprinted in a tissue-specific manner, with the paternal allele poorly expressed in some tissues. This most likely explains why maternal transmission of AHO leads to multihormone resistance and obesity while paternal transmission does not. Studies in mouse models and patients with isolated parathyroid hormone resistance (pseudohypoparathyroidism type 1B) have identified a region important for Gsα imprinting, and ongoing investigations are defining the mechanisms involved.

The Section also studies the role of these and other G proteins in other processes, particularly how they regulate energy balance (weight) and glucose metabolism. These studies may have important implications for basic understanding of the mechanisms underlying obesity and diabetes.