Dataset Information

A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

ABSTRACT:

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.

SUBMITTER: Maver A

PROVIDER: S-EPMC9528970 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

Maver Ales A Zigman Tamara T Rangrez Ashraf Yusuf AY Coric Marijana M Homolak Jan J Saric Dalibor D Skific Iva I Udovicic Mario M Zekusic Marija M Saleem Umber U Laufer Sandra D SD Hansen Arne A Frey Norbert N Baric Ivo I Peterlin Borut B

Cold Spring Harbor molecular case studies 20220715

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 35840178

Similar Datasets

Project description:Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome-wide scan with microsatellite markers and genetic linkage analysis in a 4-generation family inflicted with autosomal-dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1-q13.3, a 4.77-cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2-point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole-exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7. Add, the E144X-mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.

Dataset Information

A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

Purpose

Methods

Results

Conclusion

Publications

A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

Similar Datasets

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