Adhesion Molecules-28

Advances and Experimental-3

Aging-9

Agricultural Biotechnology-37

Angiogenesis-29

Antisense-4

Apoptosis-49

Atherosclerosis-12

Autoimmunity-69

Bacterial Virulence-18

Bioinformatics-13

BioMaterials-18

Biosurfactants-1

Biotechnology-99

Cancer Genetics-25

Cancer Metastasis-19

Cell Biology-16

Cell Cycle-34

Cell Metabolism-327

Channels and Transporters-79

Chaperones-11

Circadian Rhythms-13

Coagulation-14

Cytokines/Growth Factors-52

Development-223

DNA-56

DNA Surveillance and Repair-42

Drug Design-17

Endocrine-66

Evolution-33

Extracellular Matrix-30

Gastroenterology-52

Gene Expression-178

Gene Therapy-53

Heart-61

Heat Shock Proteins-19

Hematology-11

Immunology-93

Infectious Disease-71

Ischemia-Reperfusion-33

Leptin and Leptin Antagonists-1

Medical-20

MHC-17

Mitochondria-17

Molecular Biology-15

Molecular Complexes and Signaling-1

Nanomedicine-30

Neurodegenerative Disease-72

Neuropharmacology-112

Neuroscience-38

Nucleus-15

Oncogenes-8

Oncology-87

Parasitic Disease-12

Pharmacogenomics-14

Prebiotic Evolution-2

Protein-12

Reproductive Biology-59

RNA-152

Signal Transduction-186

Stem Cells-80

Surgery-37

T-Cell Activation-12

Tissue Engineering-116

Transplant-51

Vaccines-82

Viruses-85

Chapter category: Gene Expression

The GNAS locus and Pseudohypoparathyroidism

Chapter authors:
Murat Bastepe

Pseudohypoparathyroidism (PHP) is a disorder of end-organ resistance primarily affecting the actions of parathyroid hormone (PTH). Genetic defects associated with different forms of PHP involve the a-subunit of the stimulatory G protein (Gsa), a signaling protein essential for the actions of PTH and many other hormones. Heterozygous inactivating mutations within Gsa-encoding GNAS exons are found in patients with PHP-Ia, who also show resistance to other hormones and a constellation of physical features called Albright’s hereditary osteodystrophy (AHO). Patients who exhibit AHO features without evidence for hormone resistance, who are said to have pseudopseudohypoparathyroidism (PPHP), also carry heterozygous inactivating Gsa mutations. Maternal inheritance of such a mutation leads to PHP-Ia, i.e., AHO plus hormone resistance, while paternal inheritance of the same mutation leads to PPHP, i.e., AHO only. This imprinted mode of inheritance for hormone resistance can be explained by the predominantly maternal expression of Gsa in certain tissues, including renal proximal tubules. Patients with PHP-Ib lack coding Gsa mutations but display epigenetic defects of the GNAS locus, with the most consistent defect being a loss of imprinting at the exon A/B differentially methylated region (DMR). This epigenetic defect presumably silences, in cis, Gsa expression in tissues where this protein is derived from the maternal allele only, leading to a marked reduction of Gsa levels. The familial form of PHP-Ib (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR. A unique 3-kb microdeletion that disrupts the neighboring STX16 locus has been identified in this disorder and appears to be the cause of the loss of imprinting. In addition, deletions removing the entire NESP55 DMR, located within GNAS, have been identified in some AD-PHP-Ib kindreds in whom affected individuals show loss of all the maternal GNAS imprints. Mutations identified in different forms of PHP-Ib thus point to different cis-acting elements that are apparently required for the proper imprinting of the GNAS locus. Most sporadic PHP-Ib cases also have imprinting abnormalities of GNAS that involve multiple DMRs, but the genetic lesion(s) responsible for these imprinting abnormalities remain to be discovered.

Murat Bastepe
Massachusetts General Hospital and Harvard Medical School

» Access chapter for $19

Additional chapters from this book: