Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies.
Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies.
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DOI：
10.1016/j.ymgme.2009.04.001
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发表时间：
2009-08
影响因子：
3.8
通讯作者：
Mudd, S. Harvey
中科院分区：
文献类型：
--
作者：
Kraus, Jan P.;Hasek, Jindrich;Kozich, Viktor;Collard, Renata;Venezia, Sarah;Janosikova, Bohumila;Wang, Jian;Stabler, Sally P.;Allen, Robert H.;Jakobs, Cornelis;Finn, Christine T.;Chien, Yin-Hsiu;Hwu, Wuh-Liang;Hegele, Robert A.;Mudd, S. Harvey
我们报告了六个血浆和/或尿液中胱硫氨酸显著升高的个体的研究。对编码胱硫氨酸γ裂解酶基因Cth的研究发现，在这些个体中存在一个新的大片段缺失的纯合子或复合杂合子形式，p.Gly57_Gln196del，两个新的错义突变，c.589C>；T(p.Arg197Cys)和c.932C>；T(p.Thr311Ile)，以及一个先前报道的突变c.200C>；T(p.Thr67Ile)。另一种新的错义突变c.185G>；T(p.Arg62His)在一个台湾家庭的三个轻度高胱硫氨酸血症成员中被发现。在1例严重高胱硫氨酸血症患者中，未发现Cth突变。简要介绍了胱硫氨酸血症/胱硫氨酸尿症患者的临床病史。大多数新突变都得到了表达，并测定了突变蛋白的Cth活性。讨论了人类酶hCTH的晶体结构，以及所讨论的突变和先前报道的P.Gln240Glu对蛋白质结构、酶活性和对维生素B6注射的反应性的影响的现有证据。在健康的捷克对照组中，9.3%的人存在Cth c.1208G和Gt；T(p.Ser403Ile)纯合子，此前在测定血浆总同型半胱氨酸(THcy)的加拿大人中发现了7.5%的纯合子。与野生型纯合子相比，在55个捷克c.1208G>；T(p.Ser403Ile)纯合子中，只有在蛋氨酸加载后才发现血浆胱硫氨酸水平更高。在Cth突变失活的四个纯合子或复合杂合子个体中，有三个人的血浆tHcy水平轻度升高，可能表明存在因果关系。目前患者的经验没有证据表明严重的CTH活性丧失伴随着不良的临床效果。
We report studies of six individuals with marked elevations of cystathionine in plasma and/or urine. Studies of CTH, the gene that encodes cystathionine γ-lyase, revealed the presence among these individuals of either homozygous or compound heterozygous forms of a novel large deletion, p.Gly57_Gln196del, two novel missense mutations, c.589C>T (p.Arg197Cys) and c.932C>T (p.Thr311Ile), and one previously reported alteration, c.200C>T (p.Thr67Ile). Another novel missense mutation, c.185G>T (p.Arg62His), was found in heterozygous form in three mildly hypercystathioninemic members of a Taiwanese family. In one severely hypercystathioninemic individual no CTH mutation was found. Brief clinical histories of the cystathioninemic/cystathioninuric patients are presented. Most of the novel mutations were expressed and the CTH activities of the mutant proteins determined. The crystal structure of the human enzyme, hCTH, and the evidence available as to the effects of the mutations in question, as well as those of the previously reported p.Gln240Glu, on protein structure, enzymatic activity, and responsiveness to vitamin B6 administration are discussed. Among healthy Czech controls, 9.3% were homozygous for CTH c.1208G>T (p.Ser403Ile), previously found homozygously in 7.5% of Canadians for whom plasma total homocysteine (tHcy) had been measured. Compared to wild-type homozygotes, among the 55 Czech c.1208G>T (p.Ser403Ile) homozygotes a greater level of plasma cystathionine was found only after methionine loading. Three of the four individuals homozygous or compound heterozygous for inactivating CTH mutations had mild plasma tHcy elevations, perhaps indicating a cause-and-effect relationship. The experience with the present patients provides no evidence that severe loss of CTH activity is accompanied by adverse clinical effects.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Steegborn, C;Clausen, T;Wahl, MC
通讯作者：
Wahl, MC
影响因子：
2.9
作者：
Zhu, Weidong;Lin, Alexander;Banerjee, Ruma
通讯作者：
Banerjee, Ruma
影响因子：
3.8
作者：
Janosíková, B;Pavlíková, M;Kozich, V
通讯作者：
Kozich, V
影响因子：
3.5
作者：
Wang, J;Huff, AM;Hegele, RA
通讯作者：
Hegele, RA