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The Stimulatory G Protein -Subunit G_s Is Imprinted in Human Thyroid Glands: Implications for Thyroid Function in Pseudohypoparathyroidism Types 1A and 1B

Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Lee S. Weinstein, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Building 10, Room 8C101, Bethesda, Maryland 20892-1752. E-mail: leew{at}amb.niddk.nih.gov.

The stimulatory G protein -subunit G_s couples receptors to adenylyl cyclase and is required for hormone-stimulated cAMP generation. In Albright hereditary osteodystrophy, heterozygous G_s null mutations only lead to PTH, TSH, and gonadotropin resistance when inherited maternally [pseudohypoparathyroidism type 1A; (PHP1A)]. Maternal-specific expression of G_s in specific hormone targets could explain this observation. Using hot-stop PCR analysis on total RNA from six normal human thyroid specimens, we showed that the majority of the G_s mRNA (72 ± 3%) was derived from the maternal allele. This is consistent with the presence of TSH resistance in patients with maternal G_s null mutations (PHP1A) and the absence of TSH resistance in patients with paternal G_s mutations (pseudopseudohypoparathyroidism). Patients with PTH resistance in the absence of Albright hereditary osteodystrophy (PHP1B) have an imprinting defect of the G_s gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific G_s deficiency. We found evidence of borderline TSH resistance in 10 of 22 PHP1B patients. This study provides further evidence for tissue-specific imprinting of G_s in humans and provides a potential mechanism for mild to moderate TSH resistance in PHP1A and borderline resistance in some patients with PHP1B.

Present address for B.E.: University of Texas Austin, Austin, Texas 78712.

Abbreviations: AHO, Albright hereditary osteodystrophy; PHP1A, pseudohypoparathyroidism type 1A; PPHP, pseudopseudohypoparathyroidism.

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