William F. Simonds, M.D.

Senior Investigator

Endocrine Signaling and Oncogenesis Section, Metabolic Diseases Branch

NIDDK

Building 10, Room 8C101
10 Center Drive
Bethesda, MD 20814

301-496-9299

wfs@mail.nih.gov

Research Topics

Research Goal

The purpose of my research is to try to understand the causes of parathyroid tumors, including malignant parathyroid tumors, and to understand the regulation of G protein signaling in brain and hormonal tissue.​

Current Research

There are two principal areas of research in my laboratory.  The first 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 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 widely expressed, evolutionarily conserved gene encoding parafibromin, a predominantly nuclear protein of 531 amino acids.  Parafibromin is a component of the evolutionarily conserved PAF1 transcriptional regulatory complex.  CDC73/HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and parathyroid cancer.  Current studies employ mammalian and Drosophila model systems to explore the key molecular mechanisms by which loss of parafibromin function promotes neoplasia.

The other focus of research in my laboratory 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 G β5 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, an acylated SNARE-like protein), are unexplained by current models of G protein signalling.  We are seeking to better understand the function of the highly conserved Gβ5/ R7 RGS protein heterodimers in brain and neuroendocrine cells.

Applying our Research

This research may help in the diagnosis and therapy of benign and malignant parathyroid tumors, and perhaps other types of 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.

Need for Further Study

Further research is required to explore other tumors or malignancies that might be related to inactivation of the CDC73/HRPT2 gene.

Biography

  • M.D., University of Pittsburgh School of Medicine, 1981
  • B.S. Physics, University of Pittsburgh College of Arts and Sciences, 1975

Selected Publications

  1. Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, Kebebew E, Biesecker LG, Simonds WF, Marx SJ, Agarwal SK. GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism. Am J Hum Genet. 2016;99(5):1034-1044.

  2. Lodder EM, De Nittis P, Koopman CD, Wiszniewski W, Moura de Souza CF, Lahrouchi N, Guex N, Napolioni V, Tessadori F, Beekman L, Nannenberg EA, Boualla L, Blom NA, de Graaff W, Kamermans M, Cocciadiferro D, Malerba N, Mandriani B, Coban Akdemir ZH, Fish RJ, Eldomery MK, Ratbi I, Wilde AA, de Boer T, Simonds WF, Neerman-Arbez M, Sutton VR, Kok F, Lupski JR, Reymond A, Bezzina CR, Bakkers J, Merla G. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. Am J Hum Genet. 2016;99(3):786.

  3. Zhang JH, Pandey M, Seigneur EM, Panicker LM, Koo L, Schwartz OM, Chen W, Chen CK, Simonds WF. Knockout of G protein β5 impairs brain development and causes multiple neurologic abnormalities in mice. J Neurochem. 2011;119(3):544-54.

  4. Simonds WF. Genetics of Hyperparathyroidism, Including Parathyroid Cancer. Endocrinol Metab Clin North Am. 2017;46(2):405-418.

  5. Pandey M, Zhang JH, Mishra SK, Adikaram PR, Harris B, Kahler JF, Loshakov A, Sholevar R, Genis A, Kittock C, Kabat J, Ganesan S, Neubig RR, Hoon MA, Simonds WF. A central role for R7bp in the regulation of itch sensation. Pain. 2017;158(5):931-944.


This page was last updated on March 6th, 2017