Clinical Implications of Genetic Defects in G Proteins: The Molecular Basis of McCune-Albright Syndrome and Albright Hereditary Osteodystrophy

Ringel, Matthew D.; Schwindinger, William F.; Levine, Michael A.

doi:10.1097/00005792-199607000-00001

Cited by 152 publications

(105 citation statements)

References 139 publications

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“…In endocrine glands, receptor͞G protein-activating mutations produce a phenotype of hyperstimulation or end-organ autonomous function (34). A similar phenotype would be predicted by inactivation of a PDE gene because the decrease in the rate of cAMP degradation would be expected to cause increased cAMP signaling and chronic stimulation of the endocrine gland.…”

Section: Discussionmentioning

confidence: 95%

Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice

Jin

Richard

Kuo

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

204

136

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In eukaryotic cells, the inactivation of the cyclic nucleotide signal depends on a complex array of cyclic nucleotide phosphodiesterases (PDEs). Although it has been established that multiple PDE isoenzymes with distinct catalytic properties and regulations coexist in the same cell, the physiological significance of this remarkable complexity is poorly understood. To examine the role of a PDE in cAMP signaling in vivo, we have inactivated the type 4 cAMPspecific PDE (PDE4D) gene, a mammalian homologue of the Drosophila dunce. This isoenzyme is involved in feedback regulation of cAMP levels. Mice deficient in PDE4D exhibit delayed growth as well as reduced viability and female fertility. The decrease in fertility of the null female is caused by impaired ovulation and diminished sensitivity of the granulosa cells to gonadotropins. These pleiotropic phenotypes demonstrate that PDE4D plays a critical role in cAMP signaling and that the activity of this isoenzyme is required for the regulation of growth and fertility. I n organisms as diverse as bacteria and mammals, changes in the intracellular concentration of the second messenger cAMP control a wide range of cell functions including entry and exit from the cell cycle, differentiation, metabolism, and gene expression. Similar to that shown for the Ca 2ϩ -dependent signaling pathway (1), it has been hypothesized that the intensity and duration of the cAMP signals determine the specificity of cellular responses to different stimuli (2). The pattern of intracellular cAMP accumulation depends on the activity of cyclic nucleotide phosphodiesterases (PDEs). These enzymes are regulated during hormone and neurotransmitter stimulation (3, 4) in concert with other mechanisms that control cAMP synthesis (5) and have profound effects on cAMP levels and cell responses (3,4,6,7).To date, at least 20 PDE genes and almost 50 distinct PDE proteins have been described in mammalian cells (8). These isoenzymes are characterized by different biochemical and kinetic properties, subcellular localization, and mechanisms of regulation. However, the reason a cell requires the expression of such a large array of PDEs with an overlapping function is poorly understood. It has been speculated that each isoenzyme serves slightly different roles and its expression is necessary for the specificity of the cAMP signaling or for signal compartmentalization. Here we have addressed the question of this apparent redundancy of the cAMP-degrading machinery by studying the effect of inactivating a single PDE gene.With some rare exceptions, pharmacological inhibition of PDE activity results in an increased signaling through the cAMP-dependent pathway (9), an effect that mimics the stimulation by hormones and neurotransmitters. Although this idea may hold true for short-term pharmacological manipulations, in vivo long-term cell homeostasis and differentiation is more likely impaired by the disruption of the PDE system. If the expression of distinct PDE isoenzymes is indeed required for proper cAMP signaling,...

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Section: Discussionmentioning

confidence: 95%

Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice

Jin

Richard

Kuo

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

204

136

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“…Whereas peripheral precocious puberty (PPP) is the common initial manifestation in girls, it has been reported in only 15% of boys (3). The fact that females develop PPP more frequently than males probably explains why MAS is recognized more frequently and earlier in girls (1,3,4).…”

Section: Introductionmentioning

confidence: 99%

Regulation of spermatogenesis in McCune–Albright syndrome: lessons from a 15-year follow-up.

Luca

Mitchell²,

Wasniewska³

et al. 2008

European Journal of Endocrinology

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Context: McCune-Albright syndrome (MAS) is a disorder caused by a post-zygotic gain-of-function mutation in the gene encoding the Gs-a protein. Sexual precocity, common in girls, has been reported in only 15% of boys, and little is known on the long-term evolution of MAS in males. Objective: In a boy with MAS, we studied spermatogenesis, testis histology, and immunohistochemistry with the aim to shed light on seminiferous tubule activity. Design: A boy who presented at the age of 2.9 years with sexual precocity, monolateral macroorchidism, increased testosterone levels, and suppressed gonadotropins was followed up until the age of 18. Results: Throughout follow-up testicular asymmetry persisted and gonadotropin and testosterone pattern did not change. At the age of 18, inhibin B was undetectable while a-immunoreactive inhibin was within normal range. Anti-Mullerian hormone level was slightly subnormal. Sperm cells were 3 900 000 per ejaculate. Histology of both testes showed spermatogonia, spermatocytes, and, in some tubes, matured spermatozoa. Sertoli cells were markedly stained with anti-inhibin a-subunit antibody in both the testes. There was no immunostaining of Sertoli, Leydig, or germ cells with anti-bA or anti-bB antibody. MAS R201H mutation was identified in both the testes. Conclusion:The 15-year follow-up in this boy with MAS demonstrated that autonomous testicular activation and gonadotropin suppression persisted over time. This provides an interesting model of active spermatogenesis despite long-term FSH suppression. It also suggests that FSH is needed for the full expression of the inhibin bB-subunit gene, an expression previously reported in the germ and Leydig cells of normal adult subjects.European Journal of Endocrinology 158 921-927

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“…Esta síndrome descrita por McCune e Albright em 1930 é uma doença esporádica classicamente definida pela presença de displasia óssea fibropoliostótica, manchas "café au lait" e puberdade precoce. Variações clínicas desta tríade clássica podem ocorrer, associadas a outras endocrinopatias, tais como: hipertireoidismo, acromegalia, prolactinoma e síndrome de Cushing (34,35).…”

Section: Doenças Associadas àS Mutações Ativadoras No Gene Gnas1unclassified

Manifestações Endócrinas das Mutações da Proteína Gsalfae do Imprinting do Gene GNAS1

Fragoso

2002

Arq Bras Endocrinol Metab

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RESUMOEsta revisão resume o papel da patogênese molecular das mutações do gene da proteína G s α em doenças endócrinas. As proteínas G transmitem o sinal celular de receptores de membrana 7TM. Este sistema pode ser ativado por fotons de luz, odorantes e hormônios (LH, FSH, TSH, PTH, etc). Seu efetor é a adenilato-ciclase que induz a formação de AMPc. A proteína G inativa é heterotrimérica e associada ao GDT. Receptores que ativam a proteína G s α dissociam o GDT para GTP, enquanto a atividade intrínseca GTPase hidrolisa o GTP, mantendo a proteína G s α no estado inativo, ligado ao GDP. Mutações no gene GNAS1, que codifica a proteína G s α, alteram sítios altamente conservados (Arg 201 e Gln 227 ), críticos para a atividade GTPase, levando à ativação constitutiva do sinal celular. Tais mutações são encontradas em raros tumores endócrinos, na fibrodisplasia óssea e na síndrome de McCune Albright. Ao contrário, mutações inativadoras podem levar à osteodistrofia hereditária de Albright, se transmitidas pelo alelo paterno e pseudohipoparatireoidismo tipo Ia, se transmitidas pelo alelo materno. Em ratas com knockout, o gene Gnas sofre o fenômeno de imprinting tecido específico. Em tumores de hipófise, o gene GNAS1 também sofre imprinting com expressão preferencial do alelo materno. No pseudohipoparatireoidismo tipo Ib, um defeito do imprinting na região promotora do exon 1A do gene GNAS1 parece justificar a resistência renal isolada ao PTH. Estes exemplos ilustram como defeitos da proteína G s α podem ser responsáveis pela patogênese molecular de diferentes doenças endócrinas.

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Clinical Implications of Genetic Defects in G Proteins: The Molecular Basis of McCune-Albright Syndrome and Albright Hereditary Osteodystrophy

Cited by 152 publications

References 139 publications

Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice

Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice

Regulation of spermatogenesis in McCune–Albright syndrome: lessons from a 15-year follow-up.

Manifestações Endócrinas das Mutações da Proteína Gsalfae do Imprinting do Gene GNAS1

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