Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes
Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes
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DOI：
10.1111/j.1399-0004.2008.01079.x
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Colah, R.
中科院分区：
文献类型：
--
作者：
Kedar, P.;Hamada, T.;Colah, R.
Kedar P，Hamada T，瓦朗P，Nadkarni A，Shimizu K，Fujji H，Ghosh K，Kanno H，Colah R.在丙酮酸激酶缺陷的印度患者中具有异质性临床表型的人PKLR基因的新突变谱。临床遗传学2009：75：157-162。(C)Blackwell Munksgaard，2008年，在过去4年中发现了18例不相关的丙酮酸激酶（PK）缺陷型印度患者，其临床表型从轻度慢性溶血性贫血到重度输血依赖性疾病不等。我们在36个突变等位基因中鉴定了PKLR基因中的17个不同突变。鉴定出10个新突变：427 G> A、499 C> A、1072 G> A、1180 G> T、1216 G> A、1220 A> G、644 delG、IVS 5（+20）C > A、IVS 9（+44）C > T和IVS 9（+93）A > C。PKLR基因992 A> G、1436 G> A、1220 A> G、644 delG和IVS 9（+93）A > C突变常导致严重综合征。基于人PK的晶体结构，对人红细胞PK（RPK）的分子图形分析表明，位于底物或1，6-二磷酸果糖结合位点附近的突变可能改变活性位点的构象，导致PK活性极低，临床症状严重。突变靶向RPK结构的不同区域，包括结构域界面和催化和变构位点。特别地，1216 G> A和1219 G> A突变显著影响结构域间相互作用，因为它们位于A/B界面结构域中的催化位点附近。印度人群中最常见的突变似乎是1436 G> A（19.44%），其次是1456 C> T（16.66%）和992 A> G（16.66%）。这是第一项将临床特征与导致印度PK缺陷的分子缺陷相关联的研究，其中确定了10种产生非球形红细胞溶血性贫血的新型突变。
Kedar P, Hamada T, Warang P, Nadkarni A, Shimizu K, Fujji H, Ghosh K, Kanno H, Colah R. Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes.Clin Genet 2009: 75: 157-162. (C) Blackwell Munksgaard, 2008Eighteen unrelated pyruvate kinase (PK)-deficient Indian patients were identified in the past 4 years with varied clinical phenotypes ranging from a mild chronic haemolytic anaemia to a severe transfusion-dependent disorder. We identified 17 different mutations in the PKLR gene among the 36 mutated alleles. Ten novel mutations were identified: 427G > A, 499C > A, 1072G > A, 1180G > T, 1216G > A, 1220A > G, 644delG, IVS5 (+20) C > A, IVS9 (+44) C > T, and IVS9 (+93) A > C. A severe syndrome was commonly associated with some mutations, 992A > G, 1436G > A, 1220A > G, 644delG and IVS9 (+93) A > C, in the PKLR gene. Molecular graphics analysis of human red blood cell PK (RPK), based on the crystal structure of human PK, shows that mutations located near the substrate or fructose 1,6-diphosphate binding site may change the conformation of the active site, resulting in very low PK activity and severe clinical symptoms. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. In particular, the 1216G > A and 1219G > A mutations significantly affect the interdomain interaction because they are located near the catalytic site in the A/B interface domains. The most frequent mutations in the Indian population appear to be 1436G > A (19.44%), followed by 1456C > T (16.66%) and 992A > G (16.66%). This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non-spherocytic haemolytic anaemia were identified.