This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 (encoded by the GNAS gene) to stimulation of adenylyl cyclase. Expression of hormones, receptors, or Gs molecules with altered biological activity can result in gain or loss of hormone action. This 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 (PHP1a) and McCune Albright syndrome due to altered expression or function of Gs, pseudohypoparathyroidism type 1b due to abnormalities in the methylation of the GNAS gene, and hypoparathyroidism due to defects in the calcium-sensing receptor or PTH gene. Biochemical and clinical characterization of the patient's phenotype facilitates a laboratory-based approach to elucidating the molecular mechanism of disease. Specifically, within PHP1a, short stature and obesity are major clinical concerns. We have evaluated the clinical and endocrine characteristics of patients with PHP1a to determine whether they might have deficient secretion of GH secondary to growth hormone (GH) deficiency due to defective signal transduction of growth hormone-releasing hormone which could be the cause of the short stature and obesity. Indeed, we have found that approximately two-thirds of these patients are GH deficient (Germain-Lee et al., 2003; Germain-Lee, 2006; and unpublished results). At this point in time, we have completed screening of 34 subjects and have found evidence of GH deficiency in 22 subjects. Some of these subjects are currently in a GH treatment trial with human recombinant GH. GH treatment has preliminarily shown an improvement in one or more of the following: linear growth velocities (in children); final adult heights; weight parameters; adiposity; lipid profiles; and bone densities. Therefore, GH may improve the quality of life and overall health in this patient population. PHP1a is a sub-type of Albright hereditary osteodystrophy, a broader category which includes both PHP1a and pseudopseudohypoparathyroidism (pseudoPHP). PseudoPHP results from the same heterozygous inactivating mutations in the GNAS gene which cause PHP1a. Although patients with PHP1a and pseudoPHP have similar phenotypes, those with pseudoPHP do not have hormonal abnormalities. This difference occurs because of paternal imprinting-- ie, when the defective allele is maternal in origin, PHP1a occurs with hormonal abnormalities secondary to tissue-specific imprinting in hormonally active tissues; when the defective allele is paternal in origin, pseudoPHP occurs without hormonal abnormalities. However, pseudoPHP patients are also short even though they are not GH deficient. The short stature in both PHP1a and pseudoPHP is partially contributed to by premature fusion of the epiphyses most likely secondary to premature chondrocyte differentiation due to haploinsufficiency of G-alpha-s. We are currently investigating the impact of GH deficiency versus the premature epiphyseal fusion in the short stature phenotype. In addition, we plan to investigate the role of GH in the improvement of linear growth velocity and final adult height of those patients with PHP1a who are not GH deficient as well as patients with pseudoPHP (who, by definition, are not GH deficient). It is possible that by increasing linear growth velocity prior to epiphyseal fusion, final adult heights could be improved in these non-GH deficient patient populations as well. Classically, it has been thought that pseudoPHP patients are also obese, as in PHP1a. We have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings implicate paternal imprinting of G-alpha-s in the development of the obesity in PHP1a (Long et al, in press).
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