STUDIES OF HORMONE ACTION IN PATIENTS WITH ALTERED G PROTEIN FUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The action of many hormones requires their interaction with specific cell surface receptors that are coupled by the guanine nucleotide-binding protein Gs to stimulation of adenylyl cyclase. Expression of hormones, receptors, or Gs molecules with altered biological activity can result in gain or loss of hormone actionThis protocol examines the molecular basis for altered hormone action in signal transduction pathways that utilize Gs protein as a signal transducer. These disorders include pseudohypoparathyroidism type 1a and McCune Albright syndrome due to altered expression or function of Gs, hypoparathyroidism due to defects in the calcium-sensing receptor or PTH gene, and short stature due to defects in the growth hormone-releasing hormone receptor. Biochemical and clinical characterization of the patient's phenotype facilitates a laboratory-based approach to elucidating the molecular mechanism of disease. We have evaluated the clinical and endocrine characteristics of patients with PHP type 1a to determine whether they might have deficient secretion of growth hormone (GH). We have now completed screening of 26 subjects, and have found evidence of GH deficiency in 19 subjects. These subjects are candidates for our substudy trial of hormone replacement with human recombinant GH. GH treatment has preliminarily shown an improvement in one or more of the following: height velocity, BMI, lipid profiles, and bone densities. GH deficiency may play a role in the obesity and short stature that is common in these subjects.