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Novel IDS Variants Identified in Three Unrelated Pakistani Patients Affected with Mucopolysaccharidosis Type II (Hunter Syndrome)
Human Heredity ( IF 1.8 ) Pub Date : 2020-10-19 , DOI: 10.1159/000510065
Bibi Zubaida , Hajira Batool , Huma Arshad Cheema , Nadia Waheed , Muhammad Naeem

Introduction: Mucopolysaccharidosis type II (MPS-II) or Hunter syndrome is a rare X-linked recessive disorder caused by genetic lesions in the IDS gene, encoding the iduronate-2-sulfatase (IDS) enzyme, disrupting the metabolism of certain sulfate components of the extracellular matrix. Thus, the undegraded components, also known as glycosaminoglycans, accumulate in multiple tissues resulting in multisystemic abnormalities. Objective: To uncover causative genetic lesions in probands of three unrelated Pakistani families affected with rare X-linked recessive Hunter syndrome. Methods: Screening of the IDS gene was performed in six individuals (three patients and their mothers) through whole genomic DNA extraction from peripheral blood followed by PCR and Sanger sequencing. MutationTaster, PROVEAN, Human Splicing Finder, Swiss-Model, and SwissPdbViewer were used for in silico analysis of identified variants. Results: All probands were presented with coarse facies, recurrent respiratory tract infection, and reduced IDS activity. Molecular screening of IDS identified three different pathogenic variants including a novel duplication variant c.114_117dupCGTT, a novel splice site variant c.1006 + 1G#x3e;C, and a nonsense variant c.1165C#x3e;T. In silico analysis unanimously revealed the pathogenic nature of the variants due to their deleterious effects upon the encoded enzyme. Conclusion: Identified variants predictably lead to either the expression of a nonfunctional enzyme due to partial loss of SD1 and complete loss of SD2 subdomains or a complete lack of the IDS enzyme as a result of nonsense-mediated mRNA decay. Our study provides the first genetic depiction of MPS-II in Pakistan, expands the global IDS mutation spectrum, may provide insights into the three-dimensional structure of IDS, and should benefit the affected families in genetic counseling and prenatal diagnosis.
Hum Hered


中文翻译:

在三名不相关的II型粘多糖贮积症(猎人综合征)的巴基斯坦无关患者中鉴定出新的IDS变异体

简介: II型黏多糖贮积症(MPS-II)或Hunter综合征是由IDS基因的遗传损伤引起的一种罕见的X连锁隐性疾病,编码IDURATE-2-硫酸酯酶(IDS)酶,破坏了其中的某些硫酸盐成分的代谢细胞外基质。因此,未降解的成分(也称为糖胺聚糖)会在多个组织中积聚,从而导致多系统异常。目的:发现三个罕见的X连锁隐性亨特综合征的巴基斯坦无关家庭的先证者的致病性遗传病灶。方法:通过从外周血中提取全基因组DNA,然后进行PCR和Sanger测序,对6名个体(三名患者及其母亲)进行IDS基因筛选。MutationTaster,PROVEAN,Human Splicing Finder,Swiss-Model和SwissPdbViewer用于对鉴定出的变异进行计算机分析。结果:所有先证者均表现出粗大的相,反复呼吸道感染和IDS活性降低。IDS的分子筛查确定了三种不同的病原体变体,包括新的复制变体c.114_117dupCGTT,新的剪接位点变体c.1006 + 1G#x3e; C和无意义的变体c.1165C#x3e; T。在计算机分析中一致地揭示了变体的致病性质,因为它们对编码的酶具有有害作用。结论:鉴定的变体可预测地导致由于SD1的部分丢失和SD2子域的完全丢失而导致的非功能性酶的表达,或者由于无义介导的mRNA衰变而导致IDS酶的完全缺乏。我们的研究提供了巴基斯坦MPS-II的第一个遗传学描述,扩展了IDS的全球突变谱,可能为IDS的三维结构提供了见识,并且应该在遗传咨询和产前诊断中使受影响的家庭受益。
嗡嗡声
更新日期:2020-10-19
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