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Circ Genom Precis Med. 2019 Aug 28. doi: 10.1161/CIRCGEN.119.002507. [Epub ahead of print]

Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.

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Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Centogene AG, Rostock, Germany.
University Hospital Heidelberg, Heidelberg, Germany.


Background - Pediatric cardiomyopathies are a clinically and genetically heterogeneous group of heart muscle disorders associated with high morbidity and mortality. Although knowledge of the genetic basis of pediatric cardiomyopathy has improved considerably, the underlying cause remains elusive in a substantial proportion of cases. Methods - Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy. Protein expression was assessed in patient samples, followed by an in vitro tail-anchored protein insertion assay and functional analyses in zebrafish. Results - We identified compound heterozygous variants in the highly conserved ASNA1 gene, which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins. The c.913C>T variant on the paternal allele is predicted to result in a premature stop codon p.(Gln305*), and likely explains the decreased protein expression observed in myocardial tissue and skin fibroblasts. The c.488T>C variant on the maternal allele results in a valine to alanine substitution at residue 163 (p.Val163Ala). Functional studies showed that this variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype. Conclusions - Biallelic variants in ASNA1 cause severe pediatric cardiomyopathy and early death. Our findings point toward a critical role of the tail-anchored membrane protein insertion pathway in vertebrate cardiac function and disease.


endoplasmic reticulum; membrane proteins; pediatric; tail-anchoring


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