在 412 名汉族先天性心脏病患者中鉴定肌球蛋白家族基因中的罕见变异，并进行遗传分析。

Identification and genetic analysis of rare variants in myosin family genes in 412 Han Chinese congenital heart disease patients.

机构信息

Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering at School of Life Sciences, Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.

NHC Key Lab of Reproduction (Shanghai Institute of Planned Parenthood Research), Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.

出版信息

Mol Genet Genomic Med. 2022 Oct;10(10):e2041. doi: 10.1002/mgg3.2041. Epub 2022 Aug 22.

DOI:10.1002/mgg3.2041

PMID:35993536

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9544220/

Abstract

BACKGROUND

Myosin family genes, including those encoding myosin heavy chain 6, myosin heavy chain 7, myosin light chain 3, and myosin light chain 2 (MYL2), are important genetic factors in congenital heart disease (CHD). However, how these genes contribute to CHD in the Han Chinese population remains unclear.

METHODS

We sequenced myosin family genes in a Han Chinese cohort comprising 412 CHD patients and 213 matched controls in the present study. A zebrafish model was used to evaluate the pathogenicity of rare mutations in MYL2.

RESULTS

We identified 30 known mutations and 12 novel mutations. Furthermore, the contributions of two novel mutations, MYL2 p.Ile158Thr and p.Val146Met, to CHD were analyzed. The p.Ile158Thr mutation increased MYL2 expression. In zebrafish embryos, injection of myl2b-targeting morpholinos led to aberrant cardiac structures, an effect that was reversed by expression of wild-type MYL2 but not MYL2 p.Ile158Thr and pVal146Met.

CONCLUSIONS

Overall, our findings suggest that MYL2 p.Ile158Thr and p.Val146Met contribute to the etiology of CHD. The results also indicate the importance of MYL2 in heart formation.

摘要

背景

肌球蛋白家族基因，包括编码肌球蛋白重链 6、肌球蛋白重链 7、肌球蛋白轻链 3 和肌球蛋白轻链 2（MYL2）的基因，是先天性心脏病（CHD）的重要遗传因素。然而，这些基因如何导致汉族人群发生 CHD 尚不清楚。

方法

本研究对一个汉族人群进行了肌球蛋白家族基因测序，该人群包括 412 例 CHD 患者和 213 例匹配对照。我们还使用斑马鱼模型评估了 MYL2 中罕见突变的致病性。

结果

我们鉴定了 30 个已知突变和 12 个新突变。此外，还分析了两个新突变 MYL2 p.Ile158Thr 和 p.Val146Met 对 CHD 的贡献。p.Ile158Thr 突变增加了 MYL2 的表达。在斑马鱼胚胎中，注射靶向 myl2b 的莫洛尼氏菌导致心脏结构异常，而表达野生型 MYL2 可逆转该效应，但 MYL2 p.Ile158Thr 和 pVal146Met 则不能。