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G protein defects in signal transduction
1National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
G proteins couple receptors for many hormones to effectors that regulate second messenger metabolism. Several endocrine disorders have been shown to be caused by either loss- or gain-of-function mutations in G proteins or G protein-coupled receptors. In pseudohypoparathyroidism type Ia (PHP Ia), there are generalized hormone resistance (parathyroid hormone [PTH], thyroid-stimulating hormone, gonadotropins) and associated abnormal physical features, Albright hereditary osteodystrophy. Subjects with PHP Ib are normal in appearance and show renal resistance to PTH. In McCune-Albright syndrome (MAS), subjects show autonomous endocrine hyperfunction associated with fibrous dysplasia of bone and skin hyperpigmentation. Germline loss-of-function mutations have been identified in the G(s)-alpha gene in PHP Ia, and recent evidence suggests that the G(s)-alpha gene is paternally imprinted in a tissue-specific manner. Abnormal imprinting of the G(s)-alpha gene may be the cause of PHP Ib. MAS, in contrast, is caused by gain-of-function missense mutations of the G(s)-alpha gene.
Insights
Mutations in the G(s)-alpha gene cause endocrine disorders like pseudohypoparathyroidism (PHP Ia and Ib) and McCune-Albright syndrome (MAS). These conditions involve hormone resistance or hyperfunction due to altered G protein signaling.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- G proteins are crucial intermediaries linking hormone receptors to intracellular signaling pathways.
- Dysfunction in G proteins or their receptors can lead to various endocrine disorders.
- Pseudohypoparathyroidism (PHP) and McCune-Albright syndrome (MAS) are examples of G protein-related endocrine diseases.
Purpose of the Study:
- To elucidate the genetic basis of endocrine disorders related to G protein signaling.
- To differentiate the molecular mechanisms underlying PHP Ia, PHP Ib, and MAS.
- To investigate the role of G(s)-alpha gene mutations and imprinting in these conditions.
Main Methods:
- Genetic analysis to identify mutations in the G(s)-alpha gene.
- Analysis of G(s)-alpha gene imprinting patterns in affected individuals.
- Phenotypic correlation with identified genetic defects.
Main Results:
- Loss-of-function mutations in the G(s)-alpha gene are identified in pseudohypoparathyroidism type Ia (PHP Ia).
- Evidence suggests tissue-specific paternal imprinting of the G(s)-alpha gene.
- Abnormal imprinting of the G(s)-alpha gene is implicated in pseudohypoparathyroidism type Ib (PHP Ib).
- Gain-of-function missense mutations in the G(s)-alpha gene cause McCune-Albright syndrome (MAS).
Conclusions:
- Germline mutations in the G(s)-alpha gene are central to PHP Ia and MAS.
- Aberrant G(s)-alpha gene imprinting is a likely cause of PHP Ib.
- These findings highlight the critical role of G(s)-alpha signaling and its regulation in endocrine function and development.