Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
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DOI：
10.1371/journal.pone.0032065
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Valentini G
中科院分区：
文献类型：
--
作者：
Chiarelli LR;Morera SM;Bianchi P;Fermo E;Zanella A;Galizzi A;Valentini G
磷酸甘油酸激酶（PGK）催化糖酵解中重要的ATP生成步骤。PGK 1缺乏症是一种罕见的X连锁遗传性疾病，通常以非球形红细胞溶血性贫血、神经功能障碍和肌病的各种组合为特征。患者很少表现出所有三种临床特征。为了提供一个不同的病理表现的分子框架，所有已知的突变进行了审查和16突变酶，获得重组形式，功能和结构特征。大多数突变严重影响热稳定性，并在不同程度上影响催化效率，这与临床上在患者中观察到的显著低的PGK活性一致。严重损害蛋白质稳定性但中度影响动力学特性的突变（p.I47N、p.L89P、p.C316R、p.S320N和p.A354P）与临床表型呈现最同质的相关性。携带这些突变的患者表现出溶血性贫血和神经系统疾病，并且除了p.A354P变体之外，没有近视。在催化效率（p.G158V、p.D164V、p.K191del、D285 V、p.D315N和p.T378P）和热稳定性（除了p.T378P之外的所有）方面高度扰动的变体导致主要与单独的肌病相关。最后，轻微影响分子特性的突变（p.R206P、p.E252A、p.I253T、p.V266M和p.D268N）与广泛的临床症状相关。这些是第一个将临床症状与突变酶的分子特性相关联的研究。所有的研究结果表明，不同的临床表现与PGK 1缺乏症主要取决于不同类型的扰动所造成的突变PGK 1基因，突出需要确定的PGK变体的分子特性，以协助预后和遗传咨询。然而，仅根据突变酶的分子特性不能理解临床症状。不同的（环境，代谢，遗传和/或表观遗传）干预因素可以促进PGK缺乏的临床表型的表达。
Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.
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影响因子：
15
作者：
Cliff, Matthew J.;Bowler, Matthew W.;Waltho, Jonathan P.
通讯作者：
Waltho, Jonathan P.
影响因子：
4.8
作者：
Krishnan, P;Gullen, EA;Cheng, YC
通讯作者：
Cheng, YC
影响因子：
6.5
作者：
Flanagan, Jonathan M.;Rhodes, Melissa;Beutler, Ernest
通讯作者：
Beutler, Ernest
DOI：
10.1073/pnas.82.20.6965
发表时间：
1985-01-01
影响因子：
11.1
作者：
MICHELSON, AM;BLAKE, CCF;ORKIN, SH
通讯作者：
ORKIN, SH
DOI：
10.1073/pnas.78.4.2587
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
FUJII, H;CHEN, SH;YOSHIDA, A
通讯作者：
YOSHIDA, A