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PubMed1998

Diminished responsiveness of Gs-coupled receptors in severely failing human hearts: no difference in dilated versus ischemic cardiomyopathy.

In end-stage heart failure, cardiac beta-adrenoceptors are decreased and cardiac Gi protein is increased. We assessed beta-adrenoceptors, G proteins, and effects of several beta-adrenoceptor agonists, histamine, and 5-HT on adenylyl cyclase activity in right and left atria and left ventricles and on left ventricular contractility in six potential heart transplant donors (nonfailing hearts; NFHs) and in nine patients with end-stage dilated cardiomyopathy (DCM) and 11 patients with end-stage ischemic cardiomyopathy (ICM) to establish whether the functional responsiveness of all cardiac Gs-coupled receptors is reduced. Beta-adrenoceptors were reduced in all three tissues; in DCM, beta1-adrenoceptors were more markedly downregulated; in ICM, both beta1- and beta2-adrenoceptors were diminished. In all three tissues, isoprenaline-, terbutaline-, histamine- and 5-HT-induced adenylyl cyclase activation was reduced similarly in DCM and ICM. Moreover, in DCM and ICM, guanosine triphosphate (GTP)- (involving Gs and Gi) activated adenylyl cyclase was significantly diminished, whereas NaF-activated (involving only Gs) and Mn2+-activated (acting at the catalytic unit of the enzyme) adenylyl cyclase was unaltered. Left ventricular positive inotropic responses to beta1- (noradrenaline, dopamine, and dobutamine), beta2- (terbutaline), and beta1- and beta2-adrenoceptors (isoprenaline, adrenaline, and epinine), as well as H2-receptor (histamine) stimulation were significantly reduced. The extent of reduction was not different for each agonist in ICM and DCM. We conclude that in DCM and ICM, functional responsiveness of all cardiac Gs-coupled receptors is similarly reduced.

Adenylyl Cyclases↗

PubMed2005

Corneal graft survival after prolonged storage in Optisol-GS.

PURPOSE: To evaluate the outcome of corneal transplants performed with donor corneas that had been stored for prolonged (>168 hours) periods of time in Optisol-GS storage media. METHODS: A retrospective review was performed of the medical records of every patient who underwent corneal transplantation between January 1, 1999 and December 31, 1999 utilizing donor tissue that had been in Optisol-GS storage medium for more than 168 hours. RESULTS: Two hundred thirty-four corneal transplants met the inclusion criteria. The mean duration of follow-up was 33.7 +/- 14.7 months (range 2 to 56 months). The mean Optisol-GS storage time was 237.1 +/- 41.6 hours (range 168 to 348 hours). The overall graft survival rate was 78.6%, ranging from a high of 100% for keratoconus to a low of 42.9% for therapeutic grafts. The likelihood of graft survival, of achieving a visual outcome of 20/40 or better, or of suffering a visual outcome of 20/200 or worse, was not statistically significantly affected by progressively longer periods of donor storage time for the entire study population or for any recipient diagnosis. There were no cases of primary graft failure or early (<3 months) microbial keratitis. An epithelial defect was present on the first postoperative day in every eye. Increased donor storage time was associated with a statistically significant increased risk of persistence of the postoperative epithelial defect for more than 7 days (P = 0.01) as well as for more than 14 days (P = 0.008), although the presence of a postoperative persistent epithelial defect did not have a statistically significant adverse impact on graft survival or visual outcome. CONCLUSION: Satisfactory surgical outcomes can be achieved utilizing donor corneas that have been stored in Optisol-GS media for more than 7 days. Ophthalmologists utilizing such tissue should be cognizant of the inevitability of postoperative epithelial defects in these cases as well as increased likelihood of development of persistent epithelial defects.

Cell Count↗

PubMed1989

Characterization of a cell-surface protein antigen of hydrophilic Streptococcus mutans strain GS-5.

Fourteen strains of Streptococcus mutans serotype c were examined for their cell-surface protein antigens in terms of hydrophobicity, Mr and immunochemical specificities. Thirteen strains were hydrophobic, while strain GS-5 was markedly hydrophilic as compared to the other strains tested. Cell-surface protein antigens were then analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western immunoblotting. A protein antigen of Mr 190,000 (PAc) was found in cell extracts and culture supernatants of all the hydrophobic strains. Neither culture supernatant nor cell extract of strain GS-5 contained PAc. Strain GS-5, however, produced extracellularly a large amount of a protein of Mr 155,000 (PAGS-5) which reacted with rabbit anti-PAc serum. Immunodiffusion analysis showed that PAGS-5 lacked a part of the antigenic moieties in the PAc molecule. SDS-PAGE and radioimmunoassay showed a small amount of PAGS-5 on the cell surface of strain GS-5. These findings suggest that PAGS-5 may correspond to PAc which lacks a region participating in binding of PAc to the streptococcal cell.

Antigens, Bacterial↗

PubMed1995

Point mutations of ras and Gs alpha subunit genes in thyroid tumors.

We studied 43 thyroid tumors including 5 adenomatous goiters, 7 follicular adenomas, 22 papillary carcinomas, and 9 medullary carcinomas with regard to the presence of point mutations in the genes of Gs alpha subunit (Gs alpha), Gi2 alpha subunit (Gi2 alpha), H-ras, K-ras, and N-ras by a polymerase chain reaction-direct sequencing method. An adenomatous goiter and a follicular adenoma showed double mutations at codon 227 and 231, and 4 papillary carcinomas showed mutation at codon 231 of the Gs alpha gene. An adenomatous goiter, a follicular adenoma, and a papillary carcinoma showed a missense mutation in codon 13 of the K-ras gene. There were no such missense mutations of these G-protein or ras genes in medullary carcinomas. These data indicate that the genetic events involved in the oncogenesis of parafollicular C-cells are different from those of thyroid follicular cells, in which missense mutations of Gs alpha and ras genes seem to play important roles in tumorigenesis.

Base Sequence↗

PubMed1999

Differences in substrate specificity among glutathione conjugates (GS-X) pump family members: comparison between multidrug resistance-associated protein and a novel transporter expressed on a cisplatin-resistant cell line (KCP-4).

The substrate specificity of primary active transporters expressed on two kinds of human epidermoid KB-3-1 derived cell lines, C-A500 and KCP-4, was examined; the former expresses multidrug resistance-associated protein (MRP1), whereas the latter is resistant to cis-diamminedichloroplatinum (II) (cisplatin). Northern blot analysis indicated that neither P-glycoprotein, MRP1, MRP2 (canalicular multispecific organic anion transporter; cMOAT) nor MRP3 was overexpressed on KCP-4. Membrane vesicles isolated from C-A500 and KCP-4, but not from KB-3-1, exhibited the ATP-dependent uptake of glutathione conjugates (GS-X) such as leukotriene C4 and 2,4-dinitrophenyl-S-glutathione (DNP-SG), indicating the presence of GS-X pumps on these cells. The uptake of these GS-X by membrane vesicles from C-A500 was approximately twice that in the case of KCP-4. Kinetic analysis indicated that the Km and Vmax values for DNP-SG uptake were 2.56 and 1.43 microM, and 570 and 160 pmol/min/mg protein for C-A500 and KCP-4, respectively. In marked contrast, significant ATP-dependent uptake of glutathione-platinum complex was observed only in membrane vesicles from KCP-4, but not those from KB-3-1 and C-A500. The transport properties of estradiol-17beta-D-glucuronide (E(2)17betaG) were also different between the two cell lines. This was reflected in the findings that the ATP-dependent uptake of this conjugated metabolite in membrane vesicles from C-A500 (Km=2.33 microM, Vmax=34 pmol/min/mg protein) was much more extensive than that in the case of KCP-4 (Km=5.5 microM, Vmax=35 pmol/min/mg protein), and that comparable uptake was observed between KCP-4 and KB-3-1. Overall, a clear difference in substrate specificity among GS-X pump family members expressed on resistant tumor cells was demonstrated.

ATP-Binding Cassette Transporters↗

PubMed1991

Anti-granulocyte antibodies (C-ANCA, P-ANCA, GS-ANA) studied by confocal scanning laser fluorescence microscopy, ELISA, and chemiluminescence techniques.

Fifty-nine patient sera with antibodies against human polymorphonuclear neutrophil granulocyte (PMN) antigens, as determined primarily by indirect immunofluorescence microscopy (IIF) screening, were further analysed by enzyme-linked immunosorbent assays (ELISA). The antibodies were primarily characterized by their immunomorphological staining patterns on ethanol-fixed PMN as judged by conventional IIF microscopy, i.e. anti-neutrophil cytoplasmic antibodies (ANCA) giving a pancytoplasmic granular staining pattern (C-ANCA) or a diffuse perinuclear cytoplasmic pattern (P-ANCA), or granulocyte-specific anti-nuclear antibodies (GS-ANA) producing a homogeneous or peripheral nuclear staining pattern. The three distinct patterns were confirmed by confocal scanning laser IIF microscopy. As antigen substrates in the ELISA tests we used an extract from azurophil PMN granules, myeloperoxidase (MPO), and lactoferrin. As expected, most (but not all) of the C-ANCA positive sera turned out positive in the alpha-ELISA assay. Both P-ANCA and GS-ANA positive sera had high frequencies of antibodies against MPO. Occasional P-ANCA positive sera contained antilactoferrin antibodies. Although P-ANCA and GS-ANA in general probably represent the same type of auto-antibodies, we regard it appropriate to make a distinction between the two patterns, until the existence of 'true' granulocyte-specific ANAs has been ruled out. All sera were analysed for their ability to activate PMN in vitro as judged by the generation of a chemiluminescence (CL) response. Sera containing C-ANCA, as well as sera containing P-ANCA or GS-ANA, showed high frequencies of positive CL tests using 'resting' isolated PMN. The reactions were diminished, but not always abolished, by heat-treatment of the sera.

Autoantibodies↗

PubMed1993

Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder.

Experimental animal and peripheral blood cell studies point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective disorder. We have previously reported elevated prefrontal cortex Gs alpha protein in bipolar affective disorder and have now extended these preliminary observations in a larger number of subjects, assessing the brain regional specificity of these changes in greater detail, determining the functional biochemical correlates of such changes, and evaluating their diagnostic specificity. Membrane G protein (Gs alpha, Gi alpha, Go alpha, and G beta) immunoreactivities were estimated by western blotting in postmortem brain regions obtained from 10 patients with a DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls matched on the basis of age, postmortem delay, and brain pH. To examine whether there were functional correlates to the observed elevated Gs alpha levels, basal and GTP gamma S- and forskolin-stimulated cyclic AMP production was determined in the same brain regions. Compared with controls, Gs alpha (52-kDa species) immunoreactivity was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%), and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or cerebellum (+21%). In contrast, no significant differences were found in the other G protein subunits (Gi alpha, Go alpha, G beta) measured in these regions. Forskolin-stimulated cyclic AMP production was significantly increased in temporal (+31%) and occipital (+96%) cortex but not in other regions. No significant differences were apparent in basal or GTP gamma S-stimulated cyclic AMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

PubMed1992

Muscarinic blockade of beta-adrenoceptor-stimulated adenylyl cyclase: the role of stimulatory and inhibitory guanine-nucleotide binding regulatory proteins (Gs and Gi).

1. The functional antagonism that exists between muscarinic and beta-adrenoceptor function in guinea-pig tracheal smooth muscle was investigated by assessing Gs and Gi regulated adenylyl cyclase activity in isolated membranes. 2. Membranes from guinea-pig tracheal smooth muscle contain both Gi alpha and Gs alpha as assessed by Western blots with anti-G-protein antibodies. 3. GppNHp, a non-hydrolysable analogue of guanosine 5'-triphosphate (GTP), was shown to stimulate adenylyl cyclase activity at high concentrations (10(-6)-10(-4) M). GppNHp also produced a concentration-dependent reduction in pertussis toxin-catalysed adenosine diphosphate (ADP)-ribosylation of Gi alpha. 4. Pretreatment of tracheal smooth muscle slices with methacholine (10(-6) M) provoked a blockade of isoprenaline plus GTP, GppNHp- and GTP-stimulated adenylyl cyclase. 5. Addition of methacholine to membranes did not trigger inhibition of GTP-stimulated adenylyl cyclase activity but did block the isoprenaline-mediated augmentation of GTP-stimulated adenylyl cyclase activity. 6. Pretreatment of tracheal smooth muscle with methacholine (10(-6) M) provoked a blockade of cholera toxin-catalysed NAD(+)-dependent ADP-ribosylation of Gs alpha. 7. Phorbol-12-myristate 13-acetate (PMA)-treatment of tracheal smooth muscle slices actually enhanced GppNHp-stimulated adenylyl cyclase activity in subsequently prepared membranes. 8. We suggest that methacholine in addition to inhibiting adenylyl cyclase via a Gi-dependent mechanism induces a functional inactivation of Gs activity. These results together may explain the functional antagonism that exists between increased muscarinic tone and the ability of beta-adrenoceptor agonists to provoke excitation-contraction uncoupling.

Adenylyl Cyclases↗

PubMed1975

Antigens of Streptococcus mutans: characterization of a polysaccharide antigen from walls of strain GS-5.

A cell wall-associated polysaccharide antigen was isolated from Streptococcus mutans GS-5 and appeared to determine serotype c specificity. Ouchterlony double-diffusion analysis of crude formamide extracts derived from purified cell walls of two serotype c strains (GS-5 and JC-2) showed complete identify when reacted with anti-GS-5 sera. Immunoelectrophoresis of this extract demonstrated the typical mobility for this serotype as described by others. Column chromatography on BioGel P-100 of the crude formamide extracts derived from GS-5 walls resulted in a single antigenic peak being resolved. This material, when loaded onto a diethylaminoethylcellulose column and eluted with a linear gradient of ammonium carbonate (0.0 to 0.2 M), was resolved further into two serologically reactive peaks (I and II). Only two consituents, rhamnose and glucose, were detected in the purified column fractions. Peak 1 had a rhamnoseto-glucose molar ratio of 0.9:1.0, and peak II, the major resolvable fraction, had a molar ratio of 1.7:1.0, The peak II ratio was very similar to that found in the formamide extract residue pellet (1.6:1.0)9 Ouchterlony analysis of the crude formamide extract and the purified fractions revealed only partial identify between peaks I and II but complete identify between peak II and the crude extract. Likewise, immunoelectrophoresis showed no differences in mobility of peak II and the crude extract, whereas peak I moved towards the cathode. Possible structural relationships between the two antigenic fractions are discussed below. Hapten inhibition studies suggested that an alpha-glucosyl group is at the immunodeterminant site of the antigen.

Antigens, Bacterial↗

PubMed1991

Modulation of Gs activity by phorbol myristate acetate in rat hepatocytes.

Activation of protein kinase C promotes heterologous desensitization of hepatic adenylate cyclase. The basis for this desensitization was explored by use of a strategy with several independent approaches. Although not influencing the amount of forskolin-stimulated adenylate cyclase activity (catalyst), treatment with phorbol 12-myristate 13-acetate (PMA) decreased adenylate cyclase activation in response to either sodium fluoride or guanylyl imidodiphosphate [Gpp(NH)p]. Adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cholera toxin-treated hepatocytes and both the basal and GTP-stimulated adenylate cyclase activity of membranes from toxin-treated cells displayed a marked reduction in response to PMA. The ability of cholate extracts of hepatocyte membranes to reconstitute beta-adrenergic-stimulated adenylate cyclase activity of membrane of S49 mouse lymphoma cyc- cells was reduced by treatment with PMA. Cholera toxin-catalyzed labeling of Gs alpha-subunits was likewise diminished by phorbol ester treatment. Immunoblots of membranes from control or PMA-treated hepatocytes showed no difference in the amount of Gs alpha. Immunoprecipitation studies failed to detect phosphorylation of this G protein alpha-subunit. The data demonstrate that PMA induces an alteration in the functional status of Gs without altering the amount of this transmembrane signaling element. The alteration in Gs function may play a significant role in heterologous desensitization.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Constitutively active mutant GS alpha (G225T) and null-mutant G alpha i-2 (G203T) induce primitive endoderm from stem cells.

In F9 teratocarcinoma stem cells, retinoic acid induces a primitive endoderm-like phenotype and a sharp decline in G alpha i-2, a response mimicked by expression of RNA antisense to G alpha i-2 in the absence of this morphogen (D. C. Watkins, G. L. Johnson, and C. C. Malbon. Science Wash. DC 258: 1373-1375, 1992). The role of the GS alpha/G alpha i-2 axis in cellular differentiation was explored. In the absence of retinoic acid, F9 stem cells stably expressing a constitutively active mutant of GS alpha (G225T) progressed to the primitive endoderm phenotype, as judged by morphological and differentiation markers, such as tissue plasminogen activator. Although elevated in cells expressing G225T GS alpha, adenosine 3',5'-cyclic monophosphate does not mimic retinoic acid action and alone fails to induce stem cells to primitive endoderm. In the absence of retinoic acid, expression of a null mutant of G alpha i-2 (G203T) also induced stem cells to primitive endoderm. These observations establish G proteins in the GS alpha/G alpha i-2 axis as a control point for regulating progression to primitive endoderm independent of adenylate cyclase, in the present study's model of early mouse development.

Animals↗

PubMed1992

Adrenergic regulation of neonatal brown fat adenylyl cyclase and Gs alpha activity.

Norepinephrine (NE)-stimulated adenylyl cyclase (AC) activity increases during the perinatal period in rat brown adipose tissue (BAT), and this increase is associated with changes in the activities of both the catalytic subunit (C) and Gs alpha, the GTP-binding protein that mediates activation of C. The present study examined the role of the sympathetic nervous system in the postnatal sensitization of AC. The sympathetic innervation of BAT increased 7- to 13-fold after birth, and this increase was temporally correlated with the postnatal enhancement of AC responsiveness. 6-hydroxydopamine (6-HDA) treatment of neonates reduced tyrosine hydroxylase levels by greater than 90%. This treatment greatly reduced the perinatal increase in NE- and NaF-stimulated AC and completely abolished the increase in forskolin-Mn(2+)-stimulated activity. However, sympathectomy did not alter the postnatal increase in Gs alpha-specific activity and did not prevent the postnatal reduction in Gs alpha levels. These results demonstrate that the sympathetic innervation of BAT develops fully after birth and is essential for the postnatal increase in the activity of C but not of Gs alpha.

Adenylyl Cyclases↗

PubMed1997

High levels of Gs alpha in platelets of euthymic patients with bipolar affective disorder.

OBJECTIVE: Previous investigations have suggested the involvement of signal-transducing guanine-nucleotide-binding proteins (G proteins) both in the mechanism of action of lithium and in the pathophysiology of bipolar affective disorder. To determine whether such G protein abnormalities are a trait phenomenon, the authors investigated the levels of G protein alpha subunits in platelets and lymphocytes of euthymic patients with bipolar affective disorder. METHOD: Selective antibodies were used to quantitate levels of G protein alpha subunits regulating adenylylcyclase activity (Gs alpha-both 45- and 52-kDa forms- and Gil-2 alpha) and those regulating phosphoinositide turnover (Gq/11 alpha) in both platelets and lymphocytes of 44 euthymic patients with bipolar affective disorder and 27 matched comparison subjects. RESULTS: Levels of both Gs alpha 45 and Gs alpha 52 were higher in the platelets of the euthymic bipolar patients (both bipolar I and bipolar II) than in those of the comparison subjects. CONCLUSIONS: These findings are consistent with previous reports of high Gs alpha levels in bipolar affective disorder and, furthermore, suggest that such levels may be a trait abnormality for this condition.

Adult↗

PubMed1993

Antibodies raised against a peptide corresponding to a Gs alpha domain reveal a vimentin-associated protein.

In an attempt to localize the guanine nucleotide binding protein Gs alpha by immunocytochemistry, we synthetized peptides corresponding to several stretches of residues deduced from the published cDNA sequence of Gs alpha and raised antibodies against them. Among the peptides, one corresponding to residues 367-381 elicited antibodies that immunocytochemically detected, at the optical level, what appeared to be vimentin in several cells and tissues. Studies at the ultrastructural level confirmed this observation and also showed weak staining of some areas of plasma membranes of glial and nerve cells. Analysis by Western blots of rat brain subcellular fractions indicated that: (a) the protein stained by the anti-peptide antibodies was associated with the cytoskeleton; and (b) it was not vimentin but a protein of higher molecular weight, 65 KD. We accordingly suggest that the Gs alpha-derived peptide elicited two types of antibodies, one recognizing Gs alpha in fixed tissues, the other recognizing an epitope located in a vimentin-associated protein. This study emphasizes the caution that is needed when conclusions are drawn on the basis of immunocytochemical studies using antipeptide antibodies.

Amino Acid Sequence↗

PubMed1991

Abnormal guanine nucleotide regulatory protein in MVP dysautonomia: evidence from reconstitution of Gs.

We and others have used the term MVP dysautonomia for a particular subset of hyperadrenergic dysautonomia patients. The role of the stimulatory guanine nucleotide regulatory protein (Gs) in this dysautonomia was studied by cholate extraction of Gs from erythrocytes from 11 normal subjects and 14 symptomatic dysautonomic patients and reconstitution into cyc-S49 lymphoma membranes, which have normal receptor and adenylyl cyclase but lack Gs. Isoproterenol-stimulated adenylyl cyclase activity in the dysautonomia group was increased compared to that in controls [3.66 +/- 0.20 (mean +/- SE; n = 14) vs. 2.87 +/- 0.14 (n = 11) U cyc- reconstituted activity/mg erythrocyte protein; P less than 0.05]. beta-Adrenergic receptor high affinity state formation was greatest in the severely symptomatic group [KL/KH: severe symptoms, 130 +/- 48 (n = 6); mild symptoms, 33 +/- 7 (n = 7); control, 27 +/- 6 (n = 11); severe dysautonomia distinct, P less than 0.017]. Sodium dodecyl sulfate-polyacrylamide gels of cholera toxin-dependent ADP-ribosylated G-proteins yielded no gross distinction between severely symptomatic and control groups. This subset of hyperadrenergic dysautonomia patients, thus, has supercoupled beta 2-adrenergic receptors (increase in both agonist binding and cyclase activation) conferred by an abnormal Gs, whose effects on agonist binding reflect the severity of illness.

Adenosine Diphosphate Ribose↗

PubMed1993

The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms.

The development and progression of thyroid tumors are associated with phenotype-specific mutations of genes involved in growth control. Thyroid cell growth is controlled in part by the interaction of TSH with its receptor, with subsequent activation of the GTP-binding protein and its effector, adenylyl cyclase. The resulting increase in intracellular cAMP stimulates growth in thyrocytes. The TSH receptor (TSH-R) is a seven-transmembrane domain receptor. Intracellular domains of the TSH-R important for signal transduction and which may serve as targets for mutational activation have been defined. In addition, mutations at specific loci of the alpha-subunit of G-protein in human thyroid tumors have been described. We examined 92 benign and malignant neoplastic thyroid tissues for possible mutations of the intracytoplasmic domains of the TSH-R known to be involved in signal transduction and for mutations within the hot spots of Gs alpha. Screening was carried out by single strand conformation polymorphism (TSH-R) or denaturing gradient gel electrophoresis (Gs alpha) of polymerase chain reaction-amplified tumor DNA. No mutations were observed in the cytoplasmic domains of the TSH-R, except for a neutral base substitution in codon 460 (GCG [Ala]-->GCA [Ala]) in 3 tumors, which was also present in constitutional DNA from the affected individuals. A heterozygous mutation of codon 201 of Gs alpha (GGT [Arg]-CAT [His]) was observed in a nodule from an adenomatous goiter. In addition, a codon 227 mutation (CAG [Glu]-CAT [His]) was identified in a follicular adenoma. We conclude that mutational activation of the intracytoplasmatic domains of the TSH-R is not a significant mechanism of thyroid tumorigenesis, whereas putative activating mutations within exons 8 and 9 of Gs alpha occur infrequently in some benign follicular tumors.

Base Sequence↗

PubMed1994

An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a sporadic disease characterized by polyostotic fibrous dysplasia, café-au-lait spots, and multiple endocrinopathies. The etiology of fibrous dysplasia is unknown. Activating mutations of codon 201 in the gene encoding the alpha-subunit of Gs, the G-protein that stimulates adenylyl cyclase, have been found in all affected MAS tissues that have been studied. Initial attempts to amplify DNA from decalcified paraffin-embedded bone specimens from MAS patients were unsuccessful. Therefore, we analyzed DNA from frozen surgical bone specimens from five MAS patients using polymerase chain reaction and allele-specific oligonucleotide hybridization. Most of the cells in four specimens of dysplastic bone contained a heterozygous mutation encoding substitution of Arg201 of Gs alpha with His, but the mutation was barely detectable in peripheral blood specimens from the patients. Only a small amount of mutant allele was detected in a specimen of normal cortical bone from the fifth patient, although this patient had a high proportion of mutation in other, affected tissues. The mosaic distribution of mutant alleles is consistent with an embryological somatic cell mutation of the Gs alpha gene in MAS. The presence of an activating mutation of Gs alpha in osteoblastic progenitor cells may cause them to exhibit increased proliferation and abnormal differentiation, thereby producing the lesions of fibrous dysplasia.

Adenylyl Cyclases↗

PubMed1998

An inherited mutation associated with functional deficiency of the alpha-subunit of the guanine nucleotide-binding protein Gs in pseudo- and pseudopseudohypoparathyroidism.

Pseudohypoparathyroidism type Ia (PSP) is a disorder characterized by Albright's osteodystrophy, secondary hyperparathyroidism, lowered Gs activity, and resistance of the urinary cAMP excretion to exogenous PTH. The patients had raised basal serum levels of TSH and/or excessive TSH response to TRH. Here we have described a 38-bp deletion at the exon 1/intron 1 boundary of one Gs alpha allele in two mothers with pseudo-PSP and in six offsprings with PSP of a kindred with Albright's osteodystrophy. The deletion eliminates the splice donor site of exon 1. The pseudo-PSP patients presented decreased Gs activity, but normal urinary cAMP responses to PTH and normal TSH levels and responses to TRH. As monitored during 22 yr, they had normal serum levels of calcium and PTH. The findings demonstrate the same inherited functional defect of Gs alpha in two female patients with pseudo-PSP and in six of their offspring with PSP. The pathogenesis of clinical hypoparathyroidism remains to be clarified.

Adolescent↗