背景:LIPA,位于染色体10q23.2-q23.3,编码酶溶酶体酸性脂肪酶(LAL)(EC3.1.1.13)。LIPA的遗传改变导致溶酶体酸性脂肪酶缺乏症(LALD),导致脂质代谢异常并损害胆固醇和三酰甘油酯降解的先天性错误。已记录了40多种LIPA变体,然而,这项研究只关注两个。rs1051338变体(NM_000235:c.46A>C)影响外显子2中的信号肽,而位于外显子8中的rs116928232改变了剪接位点(NM_000235:c.894G>A),影响溶酶体酸性脂肪酶活性。考虑到LALD的不同临床表现和墨西哥人群中肝脏脂肪变性患病率的上升,主要是由于饮食,在本人口统计范围内对这些变异进行了调查,以发现潜在的影响因素.这项研究旨在揭示墨西哥西北部健康混血儿中rs1051338和rs116928232的频率。标志着这个人口统计学中的一个重要的遗传探索。
方法:三百十个健康混血儿对两种变异进行了PCR-RFLP分析,并对变体rs116928232进行Sanger测序。还进行了生物信息学分析以预测蛋白质变化。
结果:rs1051338(FA=0.39,p值=0.15)和rs116928232(FA=0.0016,p值=0.49)的等位基因频率与报告数据一致,而生物信息学分析使我们能够识别在这两种变体中观察到的蛋白质变化;最后,变异体之间无连锁(标准化D'=1.03,p值=0.56).
结论:等位基因频率与报告数据紧密匹配,和蛋白质结构分析证实了变体对LAL酶功能的影响。值得注意的是,这项研究标志着rs1051338和rs116928232在健康的墨西哥混血儿人群中的首次分析。
BACKGROUND: LIPA, situated on chromosome 10q23.2-q23.3, encodes the enzyme lysosomal acid lipase (LAL) (EC 3.1.1.13). Genetic alterations in LIPA lead to lysosomal acid lipase deficiency (LALD), an inborn error causing lipid metabolism anomalies and impairing cholesterol and triacylglyceride degradation. Over 40 LIPA variants have been documented, yet this study focuses on just two. The rs1051338 variant (NM_000235:c.46A>C) affects the signal peptide in Exon 2, whereas rs116928232, located in Exon 8, alters the splice site (NM_000235:c.894G>A), impacting lysosomal acid lipase activity. Considering the diverse clinical manifestations of LALD and the rising hepatic steatosis prevalence in Mexican population, mainly due to diet, these variants were investigated within this demographic to uncover potential contributing factors. This study aimed to reveal the frequency of rs1051338 and rs116928232 among healthy mestizo individuals in Northwest Mexico, marking a significant genetic exploration in this demographic.
METHODS: Three hundred ten healthy mestizo individuals underwent PCR-RFLP analysis for both variants, and Sanger sequencing was performed for variant rs116928232. Bioinformatic analysis was also performed to predict protein changes.
RESULTS: Allele frequencies for rs1051338 (FA = 0.39, p value = 0.15) and rs116928232 (FA = 0.0016, p value = 0.49) aligned with reported data, while bioinformatic analysis allowed us to identify the protein alteration observed in both variants; finally, the variants showed no linkage between them (normalized D\' = 1.03, p value = 0.56).
CONCLUSIONS: Allelic frequencies closely matched reported data, and protein structure analysis confirmed variant impacts on LAL enzyme function. Notably, this study marks the first analysis of rs1051338 and rs116928232 in a healthy Mexican mestizo population.