Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein Gs

Shenker, Andrew; Weinstein, Lee S.; Moran, Antoinette; Pescovitz, Ora Hirsch; Charest, Nancy J.; Boney, Charlotte M.; Wyk, Judson J. Van; Merino, María J.; Feuillan, Penelope; Spiegel, Allen M.

doi:10.1016/s0022-3476(05)80943-6

Cited by 307 publications

(195 citation statements)

References 42 publications

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“…Nonetheless, the speculation that the frequency of organ lesions reflects the time of mutation has gained wide acceptance. (11,12) In this view, extended or limited patterns of organ involvement as observed in patients would reflect an "earlier or later" time of mutation, respectively. This implies that the two FD-causing mutations may arise in different cells, at different times, through unknown, and perhaps different mechanisms.…”

Section: Fd As a Disease Of Embryonic Stem Cellsmentioning

confidence: 99%

Fibrous Dysplasia as a Stem Cell Disease

Riminucci

Saggio

Robey

et al. 2006

Journal of Bone and Mineral Research

108

100

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ABSTRACT:At a time when significant attention is devoted worldwide to stem cells as a potential tool for curing incurable diseases, fibrous dysplasia of bone (FD) provides a paradigm for stem cell diseases. Consideration of the time and mechanism of the causative mutations and of nature of the pluripotent cells that mutate in early embryonic development indicates that, as a disease of the entire organism, FD can be seen as a disease of pluripotent embryonic cells. As a disease of bone as an organ, in turn, FD can be seen as a disease of postnatal skeletal stem cells, which give rise to dysfunctional osteoblasts. Recognizing FD as a stem cell disease provides a novel conceptual angle and a way to generate appropriate models of the disease, which will continue to provide further insight into its natural history and pathogenesis. In addition, skeletal stem cells may represent a tool for innovative treatments. These can be conceived as directed to alter the in vivo behavior of mutated stem cells, to replace mutated cells through local transplantation, or to correct the genetic defect in the stem cells themselves. In vitro and in vivo models are currently being generated that will permit exploration of these avenues in depth.

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Section: Fd As a Disease Of Embryonic Stem Cellsmentioning

confidence: 99%

Fibrous Dysplasia as a Stem Cell Disease

Riminucci

Saggio

Robey

et al. 2006

Journal of Bone and Mineral Research

108

100

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“…The mutation is found in variable abundance in different endocrine and nonendocrine tissues, consistent with the mosaic distribution of abnormal cells generated by a somatic cell mutation early in embryogenesis. Severe disease may be associated with an earlier mutational event leading to more widespread distribution of mutated cells (5).…”

mentioning

confidence: 99%

“…Other endocrine abnormalities include hyperfunction of the thyroid and adrenal cortex, as well as excessive GH secretion. The majority of patients have abnormally elevated sex steroids with low or undetectable gonadotropin levels (5). Whereas pregnancies have been described later in life (9,10), polymenorrhea and amenorrhea due to continued gonadotropin-independent estrogen production have also been reported (11).…”

mentioning

confidence: 99%

Dynamics of Ovarian Function in an Adult Woman with McCune-Albright Syndrome

Laven¹,

Lumbroso²,

Sultan³

et al. 2001

Journal of Clinical Endocrinology & Metabolism

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“…Other features included thymic cortical atrophy, delayed kidney maturation, and delayed growth. With respect to the thymic cortical atrophy, thymic cortical hyperplasia has been reported in McCune-Albright syndrome due to constitutively activating G s α mutation (Danon & Crawford, 1987;Shenker et al, 1993). E2 m−/+ mice that survived to adulthood had low levels of energy expenditure and developed obesity (S. Yu et al, 2000).…”

Section: Mice With Disruption Of Gnas Exon 2 (E2 − )mentioning

confidence: 99%

Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology

Weinstein

Xie

Zhang

et al. 2007

Pharmacology & Therapeutics

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The heterotrimeric G protein α-subunit G s α is ubiquitously expressed and mediates receptorstimulated intracellular cAMP generation. Its gene Gnas is a complex imprinted gene which uses alternative promoters and first exons to generate other gene products, including the G s α isoform XLαs and the chromogranin-like protein NESP55, which are specifically expressed from the paternal and maternal alleles, respectively. G s α itself is imprinted in a tissue-specific manner, being biallelically expressed in most tissues but paternally silenced in a few tissues. Gene targeting of specific Gnas transcripts demonstrates that heterozygous mutation of G s α on the maternal (but not the paternal) allele leads to early lethality, perinatal subcutaneous edema, severe obesity, and multihormone resistance, while the paternal mutation leads to only mild obesity and insulin resistance. These parent-of-origin differences are the consequence of tissue-specific G s α imprinting. XLαs deficiency leads to a perinatal suckling defect and a lean phenotype with increased insulin sensitivity. The opposite metabolic effects of G s α and XLαs deficiency are associated with decreased and increased sympathetic nervous system activity, respectively. NESP55 deficiency has no metabolic consequences. Other gene targeting experiments have shown Gnas to have two independent imprinting domains controlled by two different imprinting control regions. Tissuespecific G s α knockout models have identified important roles for G s α signaling pathways in skeletal development, renal function, and glucose and lipid metabolism. Our present knowledge gleaned from various Gnas gene targeting models are discussed in relation to the pathogenesis of human disorders with mutation or abnormal imprinting of the human ortholog GNAS.

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Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein Gs

Cited by 307 publications

References 42 publications

Fibrous Dysplasia as a Stem Cell Disease

Fibrous Dysplasia as a Stem Cell Disease

Dynamics of Ovarian Function in an Adult Woman with McCune-Albright Syndrome

Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology

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