The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B.
The stimulatory G protein alpha-subunit G(s)alpha couples receptors to adenylyl cyclase and is required for hormone-stimulated cAMP generation. In Albright hereditary osteodystrophy, heterozygous G(s)alpha null mutations only lead to PTH, TSH, and gonadotropin resistance when inherited maternally [pseudohypoparathyroidism type 1A; (PHP1A)]. Maternal-specific expression of G(s)alpha 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)alpha mRNA (72 +/- 3%) was derived from the maternal allele. This is consistent with the presence of TSH resistance in patients with maternal G(s)alpha null mutations (PHP1A) and the absence of TSH resistance in patients with paternal G(s)alpha mutations (pseudopseudohypoparathyroidism). Patients with PTH resistance in the absence of Albright hereditary osteodystrophy (PHP1B) have an imprinting defect of the G(s)alpha gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific G(s)alpha 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)alpha in humans and provides a potential mechanism for mild to moderate TSH resistance in PHP1A and borderline resistance in some patients with PHP1B.
Liu
Jie
J
Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Erlichman
Beth
B
Weinstein
Lee S
LS
D000483:Alleles; D015152:Blotting, Northern; D002864:Chromogranins; D005091:Exons / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins; D006801:Humans; D009419:Nerve Tissue Proteins; D010281:Parathyroid Hormone / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism*; D011547:Pseudohypoparathyroidism / Q000235:genetics* / Q000378:metabolism*; D011556:Pseudopseudohypoparathyroidism / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000378:metabolism*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics / Q000378:metabolism; D013972:Thyrotropin / Q000502:physiology
D002864:Chromogranins; D009419:Nerve Tissue Proteins; D010281:Parathyroid Hormone; D021122:Protein Subunits; D013972:Thyrotropin; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins