Activating Mutation of GSα in McCune-Albright Syndrome Causes Skin Pigmentation by Tyrosinase Gene Activation on Affected Melanocytes

Kim, Il-Soo; Kim, Eun Ryoung; Nam, Hye Jung; Chin, Mi Ok; Moon, Young Ho; Oh, Myung Ryurl; Yeo, Un Cheol; Song, Seng; Kim, Jung Sim; Uhm, Mee Ryung; Beck, Nam Seon; Jin, Dong Kyu

doi:10.1159/000023467

Cited by 56 publications

(35 citation statements)

References 13 publications

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“…It has been shown that melanocytes from the cafe Â-au-lait spots of MAS patients have high mRNA levels of tyrosinase gene, probably responsible for alteration in skin pigmentation (142). As far as ®brous dysplasia is concerned, high levels of c-fos expression, presumably a consequence of increased adenylyl cyclase activity, have been detected in bone lesions from all MAS patients studied, consistent with the bone disorders present in transgenic mice overexpressing c-fos proto-oncogene.…”

Section: Gsp Oncogene In Mccune±albright Syndromesupporting

confidence: 65%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in endocrine diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identi®ed which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-speci®c hormone resistance observed in PHP Ia may result from tissuespeci®c imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identi®ed in endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune±Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2a have been identi®ed in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and signi®cance are still controversial. Finally, although Ga subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, b/g subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of b3 subunit variants in patients with essential hypertension.

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Section: Gsp Oncogene In Mccune±albright Syndromesupporting

confidence: 65%

G protein mutations in endocrine diseases

Lania

Mantovani

Spada

2001

European Journal of Endocrinology

100

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“…Pigmentation associated with systemic disease, such as Albright syndrome, Peutz-Jegher syndrome, Addison disease, and neurofibromatosis, occurs as Cafe´au lait macules or diffuse pigmentation involving mucosa and skin [24]. Gsa gene mutation and cAMPmediated tyrosine kinase activation in melanocytes may play important roles in the formation of pigmented lesions in Albright syndrome [25]. In Peutz-Jegher syndrome, it is suggested that the pigmented lesions develop secondary to the mutation of the LKB1 gene, which activates the Wnt/bcatenin pathway and contributes to the stimulation of melanocytes [26], thereby causing the excess production of melanin.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Pigmentation Caused by Imatinib: Report of Three Cases

Malik²,

Blaeser³

et al. 2011

Head and Neck Pathol

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“…Our findings support a structural model for GPR109A in which the nicotinic acid binding pocket is localized between TMH2, -3, and -7. The ligands of various receptors, such as the C3a receptor (Kim et al, 1999), the Ca 2ϩ -sensing receptor (Miedlich et al, 2004), the prostacyclin receptor (Stitham et al, 2003), or the vasopressin V 2 receptor (Wuller et al, 2004), are also interacting with a similar binding site on their respective receptors. Although the major binding sites for small molecule ligands of GPCRs are localized in the TM helices, there is evidence from site-directed mutagenesis experiments that certain residues in ECL2 can also particularly contribute to binding of small ligands to GPCRs (Kim et al, 1996;Zhao et al, 1996;Shi and Javitch, 2004).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Determinants of Ligand Binding to the Nicotinic Acid Receptor GPR109A (HM74A/PUMA-G)

Tunaru

Lättig²,

Kero³

et al. 2005

Mol Pharmacol

121

118

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The G-protein-coupled receptor GPR109A (HM74A/PUMA-G) has recently been shown to function as a receptor for nicotinic acid (niacin) and to mediate its antilipolytic effects. Nicotinic acid is able to strongly raise plasma levels of high-density lipoprotein cholesterol, a property that distinguishes nicotinic acid from other lipid-lowering drugs. To investigate the structural determinants of GPR109A ligand binding, we performed site-directed mutagenesis of putative ligand binding residues combined with generation of chimeric receptors consisting of GPR109A and its close relative GPR109B, which does not bind nicotinic acid. We could identify Asn86/Trp91 [transmembrane helix (TMH) 2/extracellular loop (ECL) 1], Arg111 (TMH3), Ser178 (ECL2), Phe276 (TMH7), and Tyr284 (TMH7) as amino acid residues critical for binding of nicotinic acid. Together with data from molecular modeling studies, our data suggest that the ligand binding pocket for nicotinic acid of GPR109A is distinct from that of most other group A receptors. Although Arg111 at TMH3 serves as the basic anchor point for the carboxylate ligands, the ring system of nicotinic acid is embedded between Trp91 at the junction TMH2/ECL1 and Phe276/ Tyr284 at TMH7. The heterocyclic ring is also bound to Ser178 at ECL2 via an H-bond. These data will facilitate the design of new antidyslipidemic drugs acting via GPR109A.

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Activating Mutation of GSα in McCune-Albright Syndrome Causes Skin Pigmentation by Tyrosinase Gene Activation on Affected Melanocytes

Cited by 56 publications

References 13 publications

G protein mutations in endocrine diseases

G protein mutations in endocrine diseases

Mucosal Pigmentation Caused by Imatinib: Report of Three Cases

Characterization of Determinants of Ligand Binding to the Nicotinic Acid Receptor GPR109A (HM74A/PUMA-G)

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