A genetic modifier of symptom onset in Pompe disease
A genetic modifier of symptom onset in Pompe disease
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DOI：
10.1016/j.ebiom.2019.03.048
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发表时间：
2019-05-01
期刊：
影响因子：
11.1
通讯作者：
Pijnappel, W. W. M. Pim
中科院分区：
文献类型：
--
作者：
Bergsma, Atze J.;In 't Groen, Stijn L. M.;Pijnappel, W. W. M. Pim
背景：庞贝氏症的新生儿筛查由于难以预测常见的先天性心脏病患者的症状发作而变得复杂。32 - 13 T> G（IVS I）变体/无效（即完全有害）酸性α-葡萄糖苷酶（GAA）基因型。这种剪接变异发生在90%的高加索晚发型patients中，并且与广泛的症状onset.Methods：我们分析了143名复合杂合子和10名纯合子IVS1患者的队列，我们评估了症状发作时的年龄，顺式作用单核苷酸变异（SNVs）的存在，并进行了剪接分析和酶活性测定。在复合杂合子IVS1患者中，同义变异c.510C> T在9/33例（27%）儿童期发病的IVS1等位基因上唯一存在，但在110例成年期发病的患者中不存在。来自含有c510 C> T的患者的成纤维细胞中的GAA酶活性低于不含c510 C> T的患者。通过减少泄漏的野生型剪接的程度，c.510C> T调节由IVS1变体引起的异常剪接。在肌肉细胞中也发现了c.510C> T的有害作用，肌肉细胞是庞贝氏症的主要靶细胞。在纯合子IVS1患者中，c.510C> T变异体在4/4（100%）无症状个体中不存在，在3/6（50%）有症状患者中存在。在来自纯合子IVS1患者的细胞中，c.510C> T引起减少的泄漏野生型splicing.Interpretation：c.510C> T是杂合子和纯合子IVS1患者复合的遗传修饰剂。这一发现对庞贝氏症的新生儿筛查计划很重要。(C)2019作者由爱思唯尔公司出版
Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS I) variant/null ( i.e. fully deleterious) acid a-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset.Methods: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays.Findings: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing.Interpretation: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. (C) 2019 The Authors. Published by Elsevier B.V.