Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy

• Published in: Medicine (Baltimore) Vol. 75; no. 4; pp. 171 - 184
• Main Authors: Ringel, M D, Schwindinger, W F, Levine, M A
• Format: Journal Article
• Language: English
• Published: United States 01.07.1996
• Subjects: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Fibrous Dysplasia, Polyostotic - genetics; Fibrous Dysplasia, Polyostotic - metabolism; GTP-Binding Proteins - genetics; GTP-Binding Proteins - physiology; Humans; Infant; Male; Middle Aged; Mutation; Pseudohypoparathyroidism - genetics; Pseudohypoparathyroidism - metabolism; Pseudopseudohypoparathyroidism - genetics; Pseudopseudohypoparathyroidism - metabolism; Signal Transduction; Structure-Activity Relationship
• ISSN: 0025-7974; 1536-5964
• DOI: 10.1097/00005792-199607000-00001

Inactivating and activating mutations in the gene encoding G alpha s (GNAS1) are known to be the basis for 2 well-described contrasting clinical disorders, Albright hereditary osteodystrophy (AHO) and McCune-Albright syndrome (MAS). AHO is an autosomal dominant disorder due to germline mutations in GNAS1 that decrease expression or function of G alpha s protein. Loss of G alpha s function leads to tissue resistance to multiple hormones whose receptors couple to G alpha s. By contrast, MAS results from postzygotic somatic mutations in GNAS1 that lead to enhanced function of G alpha s protein. Acquisition of the activating mutation early in life leads to a more generalized distribution of the mosaicism and is associated with the classic clinical triad of polyostotic fibrous dysplasia, endocrine hyperfunction, and café au lait skin lesions described in MAS. Acquisition of a similar activating mutation in GNAS1 later in life presumably accounts for the restricted distribution of the gsp oncogene, and is associated with the development of isolated lesions (for example, fibrous dysplasia, pituitary or thyroid tumors) without other manifestations of MAS. Tissues that are affected by loss of G alpha s function in AHO are also affected by gain of G alpha s function in MAS, thus identifying specific tissues in which the second messenger cAMP plays a dominant role in cell growth, proliferation, or function. Further investigations of the functions of G alpha s and other members of the GTPase binding protein family will provide more insight into the pathogenesis and clinical manifestations of human disease.