William F. Simonds, M.D.

Research Goal

The purpose of my research is to understand the regulation of G protein signaling, to study parathyroid tumors, and to analyze polygenic disease risk and etiology by studying ancestry-specific high risk gene variants predicted to impact function.

Current Research

There are three principal areas of research in my laboratory. The first concentrates 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 signalling; recent evidence suggests, however, that certain RGS proteins can also function as signal transducers or effectors in their own right.The observations that Gβ5 forms a tight complex with RGS proteins of the R7 subclass in the brain, and that such complexes are expressed in the cell nucleus and cytoplasm (in addition to the plasma membrane where the complex is anchored by binding to R7 binding protein), are unexplained by current models of G protein signalling. Mice missing both copies of Gnb5 (the gene that encodes Gβ5) have severe developmental delay, and humans missing both copies of GNB5 have intellectual impairment, speech and language delay, cognitive disability, and cardiac arrhythmia (see link here). We are seeking to better understand the function and protein-protein interactions of the Gβ5/ R7-RGS protein complex in the nervous system.

Another area of research aims to understand the pathogenesis and clinical spectrum of familial isolated hyperparathyroidism, parathyroid cancer, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). HPT-JT is a familial syndrome of HPT with autosomal dominant transmission and high but incomplete and variable penetrance. Some 20 percent of all affected by HPT-JT have parathyroid cancer, and nearly 20 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. We seek to improve the diagnosis and treatment options for benign and malignant parathyroid tumors.

The final area of research focuses on the analysis of polygenic disease risk and etiology. Epidemiological studies have firmly established the existence of ancestry-related disparities in various diseases. In addition to differences in environmental factors and in behaviors that may reflect sociocultural factors, genetic differences among populations of different ancestry may directly impact disparities in disease risk. This work employs a gene-function centered approach to analyze whole exome or whole genome sequence to identify ancestry-specific high-risk gene variants predicted to impact function. This analytical approach differs from, and is complementary to, genome-wide association studies. Our work focuses on polygenic diseases with significant public health impact such as type 2 diabetes mellitus and Alzheimer’s disease.

Applying our Research

This research may help in the diagnosis and therapy of benign and malignant parathyroid tumors. Better understanding of G protein-regulated signaling in brain and hormonal tissue may allow the identification of targets for therapeutic agents to selectively enhance or inhibit neuronal or hormonal signaling. Identification of important ancestry-specific risk genes for polygenic diseases may enhance risk stratification, diagnosis, and even provide insight into disease etiology.

Need for Further Study

Patients with neurologic disease due to loss of both copies of GNB5 might benefit from a deeper understanding of the function and interactions of Gβ5. Further research is needed to facilitate the diagnosis and therapy of benign and malignant parathyroid tumors and better understand other tumors or malignancies that might be related to inactivation of the CDC73/HRPT2 gene. Identification of critical ancestry-specific risk genes for polygenic diseases that impact public health may enhance risk evaluation, improve disease diagnosis, and suggest new therapeutic avenues.

Research in Plain Language

Our research focuses on three areas: (1) determining how a specialized complex of signaling proteins influences the activity of neurons (brain cells) and neuroendocrine cells (cells that release hormones), (2) understanding diseases of parathyroid (glands in the neck that control the level of calcium in the blood), and (3) improving methods to estimate the genetic risk of developing diseases influenced by variants in many genes, as early as possible.

We study a specialized group of signaling proteins that work together in a complex. These include the G protein β5 bound tightly to a regulator of G protein signaling (RGS) protein. These proteins are found in the plasma membranes and cytoplasm of brain cells and specialized brain cells that release hormones. We are trying to understand how these protein complexes work, in order to potentially control signaling between and within cells and the cells’ subsequent responses.

We also study the disease processes and impact of parathyroid cancer and an inherited form of hyperparathyroidism, the hyperparathyroidism-jaw tumor syndrome (HPT-JT). HPT-JT runs in families, and ~20 percent of people affected by HPT-JT develop parathyroid cancer. We would like to facilitate the diagnosis and therapy of benign and malignant parathyroid tumors in families and individuals with such tumors.

Finally, we want to improve the diagnosis and better estimate the genetic risk of developing diseases influenced by variants in many genes. The earlier that individuals with high genetic risk for such diseases can be identified, the better to allow initiation of preventative measures. Improved understanding of the risk genes associated with such diseases may also suggest causes and even possible approaches to therapy.