Clinical spectrum and pathogenesis of pseudohypoparathyroidism.
Clinical spectrum and pathogenesis of pseudohypoparathyroidism.
复制标题
假性甲状旁腺功能减退症的临床谱和发病机制。
DOI：
10.1023/a:1026510200264
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发表时间：
2000
影响因子：
8.2
通讯作者：
Levine,MA
中科院分区：
文献类型：
--
作者：
Levine,MA
Mammalian cells express a variety of signal transduction mechanisms that enable them to respond to extracellular stimuli. One highly conserved mechanism for transmembrane signal transduction is a modular system in which heterotrimeric (α, β, γ) guanine nucleotide binding proteins (G proteins) act as``couplers''to associate plasma membrane receptors with membrane-bound effector enzymes and ion channels. Because alterations in signal processing can influence cellular growth and function, and can often lead to disease, molecular and biochemical characterization of G protein-coupled signaling has progressed rapidly. Recent studies have identified germline and somatic mutations of G proteins and heptahelical receptors as the basis of several human disorders [1]. The most well-characterized G protein defects have been mutations in the human GNAS1 gene (20q13. 11) that encodes the α subunit of Gs, the G protein that stimulates adenylyl cyclase. Investigation of naturally occurring GNAS1 mutations has provided substantial insight into functional domains of Gαs, and in many instances has complemented or confirmed analyses of mutant α chains that were designed in the research laboratory. For example, early laboratory studies indicated that replacement of either arginine201 or glutamine227 of Gαs inhibits the intrinsic GTPase activity resulting in constitutive activation of adenylyl cyclase and increased production of cAMP [2, 3]. Subsequent human genetic analyses identified identical GNAS1 activating mutations that arose spontaneously in a subset of pituitary and thyroid adenomas [4, 5]. Similar mutations have also been found in patients with the McCune-Albright syndrome, a sporadic disorder characterized by increased hormone production and/or cellular proliferation of many tissues [6, 7]. By contrast, germline mutations of the GNAS1 gene that decrease expression or function of Gαs are present in subjects with Albright hereditary osteodystrophy (AHO [8]), an autosomal dominant disorder associated with a constellation of developmental defects. Most patients with AHO also show reduced responsiveness to parathyroid hormone (PTH) and other hormones whose receptors require Gαs to activate adenylyl cyclase, a condition termed pseudohypoparathyroidism (PHP) type Ia. Remarkably, in many families patients with PHP type Ia have relatives who have AHO and apparently normal hormonal responsiveness despite identical loss of function GNAS1 mutations. This variant is termed pseudopseudohypoparathyroidism (pseudoPHP)[9], an awkward designation that was chosen to draw attention to the physical similarities but biochemical differences to PHP type Ia.The spectrum of pseudohypoparathyroidism extends to include subjects who lack features of AHO and who have normal expression of Gαs in accessible tissues. These variants include both PHP type Ib and PHP type II, which differ significantly in their molecular pathophysiology (Table 1). Clinical and biochemical analyses of subjects with the various forms of PHP have expanded our understanding of the developmental and functional consequences of dysfunctional G protein-coupled signaling pathways, and have provided unexpected insights into the importance of cAMP as a regulator of the growth and/or function of many tissues. This review will focus on the pathophysiology of PHP, and integrate basic biological defects with their clinical implications.
