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Titolo:
Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting
Autore:
Weinstein, LS; Yu, SH; Warner, DR; Liu, J;
Indirizzi:
NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA NIDDKD Bethesda MD USA 20892 etab Dis Branch, NIH, Bethesda, MD 20892 USA Univ Louisville, Sch Dent, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40202 USA Univ Louisville Louisville KY USA 40202 al Biol, Louisville, KY 40202 USA
Titolo Testata:
ENDOCRINE REVIEWS
fascicolo: 5, volume: 22, anno: 2001,
pagine: 675 - 705
SICI:
0163-769X(200110)22:5<675:EMOSGP>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
MCCUNE-ALBRIGHT-SYNDROME; GUANINE-NUCLEOTIDE-BINDING; POLYOSTOTIC FIBROUS DYSPLASIA; PSEUDOHYPOPARATHYROIDISM TYPE-IB; RECEPTOR-MEDIATED ACTIVATION; CYCLASE COUPLING PROTEIN; TYROSINE KINASE-ACTIVITY; G(S)ALPHA GENE GNAS1; CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE RESPONSE; NONFUNCTIONING PITUITARY-TUMORS;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
416
Recensione:
Indirizzi per estratti:
Indirizzo: Weinstein, LS NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA NIDDKD Bethesda MD USA 20892 h, NIH, Bethesda, MD 20892 USA
Citazione:
L.S. Weinstein et al., "Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting", ENDOCR REV, 22(5), 2001, pp. 675-705

Abstract

The heterotrimeric G protein G(s) couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate G(s) by promoting exchange of GTP for GDP on the G(s) alpha -subunit (G(s)alpha) while an intrinsic GTPase activity of G(s)alpha that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific G(s)alpha residues (Arg(201) or Gln(227)) that are critical for the GTPase reaction lead to constitutive activation of G(s)-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, se ossifications, andmental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutationsleads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA). Studies in G(s)alpha knockout mice demonstrate that G(s)alpha is imprinted in a tissue-specific manner, being expressed primarily fromthe maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of G(s)alpha expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on G(s)alpha expression or PTH action. G(s)alpha has recently been shown to be also imprinted in human pituitary glands. The G(s)alpha gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products includingG(s)alpha, XL alphas (a novel G(s)alpha isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the G,a promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH(pseudohypoparathyroidisin type EB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of G(s)alpha. The GNAS1 imprinting defect in pseudohypoparathyroidisin type IB is predicted to decrease G(s)alpha expression in renalproximal tubules. Studies in G(s)alpha knockout mice also demonstrate thatthis gene is critical in the regulation of lipid and glucose metabolism.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 04:28:55