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Published on: August 8, 2022
A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy
Ales Maver1, Tamara Zigman2, Ashraf Yusuf Rangrez3
1Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, SI-1000 Ljubljana, Slovenia.
Insights
Genetic variants in the MYZAP gene cause severe dilated cardiomyopathy (DCM) in adolescents. This study identifies a MYZAP loss-of-function variant linked to cardiac contractile dysfunction, expanding the understanding of DCM
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
Background:
- Dilated cardiomyopathy (DCM) is a heart muscle disorder with unknown causes in about 50% of cases.
- Monogenic factors account for half of DCM diagnoses, highlighting the need for genetic research.
Purpose of the Study:
- To investigate the genetic basis of severe DCM in an adolescent family.
- To identify novel gene variants associated with cardiac dysfunction.
Main Methods:
- Exome sequencing identified a homozygous MYZAP gene variant in affected siblings.
- Heart tissue analysis included microscopy, immunohistochemistry, and Western blot.
- Patient-derived induced pluripotent stem cell cardiomyocytes were used for functional studies.
Main Results:
- A premature termination variant in MYZAP was found in both affected brothers.
- MYZAP protein deficiency was confirmed in heart tissue.
- Patient iPSC-derived cardiomyocytes exhibited significantly reduced contractile force and prolonged relaxation times.
Conclusions:
- Biallelic loss-of-function MYZAP variants are implicated in dilated cardiomyopathy.
- This finding supports the role of intercalated disc junction dysfunction in DCM pathogenesis.
- The study elucidates mechanisms contributing to cardiac contractile dysfunction in DCM.
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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