scholarly journals Minireview: GNAS: Normal and Abnormal Functions

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5459-5464 ◽  
Author(s):  
Lee S. Weinstein ◽  
Jie Liu ◽  
Akio Sakamoto ◽  
Tao Xie ◽  
Min Chen
Keyword(s):  
Differentially Methylated Region ◽  
Endocrine Tumors ◽  
Α Subunit ◽  
Tissue Specific ◽  
Albright Hereditary Osteodystrophy ◽  
Multiple Promoters ◽  
Fibrous Dysplasia Of Bone ◽  
Albright Syndrome ◽  
Key Residues ◽  
Inherited Mutations

Abstract GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein α-subunit (Gsα) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating Gsα mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating Gsα mutations lead to Albright hereditary osteodystrophy. Gsα is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific Gsα imprinting. Mouse knockout models show that Gsα and the alternative Gsα isoform XLαs that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.

scholarly journals Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting

2001 ◽  
Vol 22 (5) ◽  
pp. 675-705 ◽  
Author(s):  
Lee S. Weinstein ◽  
Shuhua Yu ◽  
Dennis R. Warner ◽  
Jie Liu
Keyword(s):  
G Protein ◽  
Knockout Mice ◽  
Proximal Tubules ◽  
Paternal Allele ◽  
Intracellular Camp ◽  
Endocrine Tumors ◽  
Maternal Allele ◽  
Α Subunit ◽  
Tissue Specific ◽  
Gsα Gene

Abstract The heterotrimeric G protein Gs 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 Gs by promoting exchange of GTP for GDP on the Gs α-subunit (Gsα) while an intrinsic GTPase activity of Gsα that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific Gsα residues (Arg201 or Gln227) that are critical for the GTPase reaction lead to constitutive activation of Gs-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, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate Gs in their target tissues (pseudohypoparathyroidism type IA). Studies in Gsα knockout mice demonstrate that Gsα is imprinted in a tissue-specific manner, being expressed primarily from the 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 Gsα expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on Gsα expression or PTH action. Gsα has recently been shown to be also imprinted in human pituitary glands. The Gsα 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 including Gsα, XLαs (a novel Gsα 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 Gsα promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), 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 Gsα. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease Gsα expression in renal proximal tubules. Studies in Gsα knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.

scholarly journals McCune-Albright Syndrome with Exophthalmos: A Case Report

2018 ◽  
Author(s):  
Jinrong Zhao ◽  
Jinguo Yu
Keyword(s):  
Clinical Practice ◽  
Fibrous Dysplasia ◽  
Skin Pigmentation ◽  
Rare Condition ◽  
Skeletal Deformity ◽  
Mccune Albright Syndrome ◽  
Case Presentation ◽  
Fibrous Dysplasia Of Bone ◽  
Albright Syndrome ◽  
Mccune Albright

Abstract Background: McCune-Albright syndrome (MAS) is a rare disease defined by the triad of polyostotic fibrous dysplasia of bone, skin spots, and precocious puberty. No available treatment is effective in changing the course of fibrous dysplasia of bone, but symptomatic patients require the rapeutic support to reduce bone pain and prevent fractures and deformities.we reported 1 case of McCune-Albright syndrome with exophthalmos in clinical practice. Case presentation:A 35-year-old female was admitted to our hospital who complained about “skin pigmentation for 35 years, vaginal bleeding for 30 years and progressive skeletal deformity for 28 years and exophthalmos for 2 years. And after the examination, she was been diagnosed with“McCune-Albright syndrome with exophthalmos”.We highlighted the pathogenesis and development of the disease in this rare condition. Conclusion: McCune-Albright syndrome with exophthalmos due to multiple fibrous dysplasia is rare but can be seen in clinical practice.

scholarly journals Tissue-specific modulation of Na, K-ATPase α-subunit gene expression in uremic rats

1994 ◽  
Vol 45 (3) ◽  
pp. 672-678 ◽  
Author(s):  
Pilar Bofill ◽  
I. Annelise Goecke ◽  
Silvia Bonilla ◽  
Miriam Alvo ◽  
Elisa T. Marusic
Keyword(s):  
Gene Expression ◽  
Subunit Gene ◽  
Α Subunit ◽  
Tissue Specific

scholarly journals Fibrous Dysplasia of Bone and McCune–Albright Syndrome: A Bench to Bedside Review

2019 ◽  
Vol 104 (5) ◽  
pp. 517-529 ◽  
Author(s):  
Iris Hartley ◽  
Maria Zhadina ◽  
Micheal T. Collins ◽  
Alison M. Boyce
Keyword(s):  
Fibrous Dysplasia ◽  
Mccune Albright Syndrome ◽  
Fibrous Dysplasia Of Bone ◽  
Albright Syndrome ◽  
Mccune Albright

Is McCune-Albright syndrome overlooked in subjects with fibrous dysplasia of bone?

2003 ◽  
Vol 142 (5) ◽  
pp. 532-538 ◽  
Author(s):  
Tamara S. Hannon ◽  
Ken Noonan ◽  
Rosemary Steinmetz ◽  
Erica A. Eugster ◽  
Michael A. Levine ◽  
...  
Keyword(s):  
Fibrous Dysplasia ◽  
Mccune Albright Syndrome ◽  
Fibrous Dysplasia Of Bone ◽  
Albright Syndrome ◽  
Mccune Albright

scholarly journals Parental Origin of Gsα Mutations in the McCune-Albright Syndrome and in Isolated Endocrine Tumors

2004 ◽  
Vol 89 (6) ◽  
pp. 3007-3009 ◽  
Author(s):  
Giovanna Mantovani ◽  
Sara Bondioni ◽  
Andrea G. Lania ◽  
Sabrina Corbetta ◽  
Luisa de Sanctis ◽  
...  
Keyword(s):  
Parental Origin ◽  
Endocrine Tumors ◽  
Mccune Albright Syndrome ◽  
Albright Syndrome ◽  
Mccune Albright

Characterization of Tissue-Specific HIF-1 and HIF-2 Regulatory Elements of the Erythropoietin Gene

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4763-4763
Author(s):  
Donghoon Yoon ◽  
Hyojin Kim ◽  
Minyoung Jang ◽  
Jihyun Song ◽  
Gregory E Arnold ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Specific Binding ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Mrna Levels ◽  
Specific Element ◽  
Α Subunit ◽  
Tissue Specific

Abstract Hypoxia regulates erythropoiesis and other essential processes via hypoxia-inducible transcription factors (HIFs). HIFs are heterodimers that consist of an α subunit (3 isotypes with significant homology; HIF-1α, HIF-2α, HIF-3α), and a common b-subunit; HIF-1 and HIF-2, in some instances exhibiting tissue- and gene-specific gene regulation. Erythropoietin (EPO) was the first identified HIF-1 target gene with the defined HIF-1 binding sequence. However, subsequent works suggested that HIF-2 also regulates EPO transcription and that there are other regulatory elements of EPO gene (i.e. Kidney Inducible Element KIE, Negative Regulatory Element NRE, and Negative Regulatory Liver specific Element NRLE). In silico analysis of the human EPO genome found two additional potential HIF-binding elements in the KIE and NRE regions. The comparative analysis of phylogenically conserved sequences of human, mouse, dog, and rat Epo genes further refined these mouse Epo gene HIF-binding elements as mKIE, mNRE1, mNRE2, and mNRLE2. We treated mice in hypoxia chamber (8% O2) and monitored changes of Epo mRNA levels in liver, kidney, brain, spleen, and bone marrow. All tested tissues increased Epo transcription during hypoxia. Bone marrow, spleen, kidney, and brain showed a peak of induction of Epo transcript at 3 hours of hypoxia treatment, while liver reached the highest level at 6 hours. Mice were sacrificed and organs were harvested, and in vivo chromatin immunoprecipitation (ChIPs) was performed with antibodies against HIF-1α and HIF- 2α and tissue-specific binding regions were defined. The results from these studies are summarized below. HIF-1 mKIE rnNRE mNRE2 mNRLE2 Norm Hyp Norm Hyp Norm Hyp Norm Hyp Liver − + − − + − ? ? Kidney − + − − + − + − Brain − + − − − + − + BM − + − − − − − + Splsen − + − − − − − + HIF-2 mKIE mNRE mNRE2 mNRLE2 Norm Hyp Norm Hyp Norm Hyp Norm Hyp “+” denotes presence and “-” absence of binding of HIF-1 and HIF-2, “?” – indicates inconclusive results. “Norm” - normoxia, “Hyp” - hypoxia. Liver − + − − − + − + Kidney + − − − + − ? ? Brain − − − − − − − + BM − − − − − − + − Spleen − + − − − − − + In conclusion, we demonstrate the differential hypoxia-induced binding of HIF-1 and HIF-2 at different HIF binding elements in the tissues known to express Epo. Further studies will be required to define the function of these HIF-1 and HIF-2 binding elements in tissue specific Epo expression and their role in health and disease.

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