MYZAP的一个双偶功能缺失变体与一种隐性重度扩张型心肌病有关。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-07-15 DOI:10.1101/mcs.a006221
Ales Maver, Tamara Zigman, Ashraf Yusuf Rangrez, Marijana Coric, Jan Homolak, Dalibor Saric, Iva Skific, Mario Udovicic, Marija Zekusic, Umber Saleem, Sandra D Laufer, Arne Hansen, Norbert Frey, Ivo Baric, Borut Peterlin
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引用次数: 0

摘要

目的:扩张型心肌病(DCM)是一种原发性心肌疾病,以左心室扩张和收缩功能障碍为特征。约 50% 的 DCM 病例可归因于单基因病因,而其余患者的病因仍无法解释:方法:我们报告了一个有两兄弟的家族,他们都患有严重的 DCM,在青少年时期发病。通过外显子组测序,我们在两兄弟的 MYZAP 基因中发现了一个同源的提前终止变体。MYZAP编码心肌粘连蛋白(myocardial zonula adherens protein),这是心肌细胞闰盘结构中的一种保守的心脏蛋白:结果:通过光镜和电子显微镜观察心肌、免疫组化和 Western 印迹分析探针患者心脏组织中的 MYZAP 蛋白,证实了该变异体的影响。使用患者诱导多能干细胞心肌细胞进行的功能表征显示,患者心肌收缩力明显降低,收缩和松弛达到峰值的时间延长,这与严重的收缩功能障碍一致:我们为双倍功能缺失MYZAP变体在扩张型心肌病中的作用提供了独立支持。该报告扩展了与心脏闰盘交界处功能障碍相关的心脏疾病谱,并揭示了导致 DCM 的机制。
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A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

Purpose: Dilated cardiomyopathy (DCM) is a primary disorder of the cardiac muscle, characterised by dilatation of the left ventricle and contractile dysfunction. About 50% of DCM cases can be attributed to monogenic causes, whereas the aetiology in the remaining patients remains unexplained.

Methods: We report a family with two brothers affected by severe DCM with onset in the adolescent period. Using exome sequencing, we identified a homozygous premature termination variant in the MYZAP gene in both affected sibs. MYZAP encodes for myocardial zonula adherens protein - a conserved cardiac protein in the intercalated disc structure of cardiomyocytes.

Results: The effect of the variant was demonstrated by light and electron microscopy of the heart muscle and immunohistochemical and Western blot analysis of MYZAP protein in the heart tissue of the proband. Functional characterization using patient-derived induced pluripotent stem cell cardiomyocytes revealed significantly lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction.

Conclusion: We provide independent support for the role of biallelic loss-of-function MYZAP variants in dilated cardiomyopathy. This report extends the spectrum of cardiac disease associated with dysfunction of cardiac intercalated disc junction and sheds light on the mechanisms leading to DCM.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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