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首页> 外文期刊>BMC Medical Genetics >Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India
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Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India

机译：成年I型Gaucher病成年患者的生化和分子特征及Leu444Pro-印度常见的Gaucher病突变的载频分析

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Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells’ lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20–40?years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality. The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients’ initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula. The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887. The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India.
机译：高雪氏病是一种罕见的泛种族疾病，由于未降解的糖脂葡糖脑苷脂在细胞溶酶体内的积累增加而发生。 β-葡萄糖苷酶（GBA）基因缺陷会导致葡萄糖脑苷脂酶缺乏。尽管该疾病主要在儿童时期诊断出来，但由于未能认识到异质的临床表现，成人的表现常常会被遗漏或发现晚。本研究包括7名无关的印度成年患者（年龄范围：20-40岁），患有脾肿大，有或没有肝肿大，血细胞减少和骨骼异常。生化研究表明先测量血浆壳三糖苷酶活性，然后对白细胞中的β-葡萄糖苷酶活性进行确认性测试。分子表征包括患者初步筛查常见的Gaucher突变（Leu444Pro）。之后，所有患者均使用双向Sanger测序进行了完整的GBA基因编码区研究。通过限制性片段长度多态性-聚合酶链反应技术，在1200名无关和健康的印度受试者中进行了常见高雪氏病突变（Leu444Pro）的人群筛选。使用Hardy-Weinberg公式计算等位基因频率。生化分析表明，所有患者的β-葡萄糖苷酶活性均显着降低。另外，五名患者血浆壳三糖苷酶活性的升高也支持了他们对高雪氏病的诊断。 Sanger测序确定了GBA基因的4例纯合变异的患者和3例复合杂合变异的患者。这项研究发现了两个以前在高雪氏病患者中未见过的错义变体（Ala448Thr和Val17Gly）。在这些患者中还发现了已知的突变，如Leu444Pro，Arg329Cys，Asp315Asn，Ser125Arg和Arg395Cys。同源性建模表明由于新的变体而使蛋白质结构不稳定。在印度人口中进行的Leu444Pro突变筛选发现有两个人是携带者。这出现了1：600的载频，野生型等位基因频率0.97113和突变等位基因频率0.02887。该研究报告了七名成人患者在GBA基因中发现的新颖和已知变体。这项研究是有关印度人口中Leu444Pro突变体等位基因的载波频率的第一份报告，这将有助于了解Gaucher病的负担和易感性，以影响印度的下一代。

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