PUBLICATION
Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy
- Authors
- Verhagen, J.M.A., van den Born, M., van der Linde, H.C., Nikkels, P.G.J., Verdijk, R.M., Kivlen, M.H., van Unen, L.M.A., Baas, A.F., Ter Heide, H., van Osch-Gevers, L., Hoogeveen-Westerveld, M., Herkert, J.C., Bertoli-Avella, A.M., van Slegtenhorst, M.A., Wessels, M.W., Verheijen, F.W., Hassel, D., Hofstra, R.M.W., Hegde, R.S., van Hasselt, P.M., van Ham, T.J., van de Laar, I.M.B.H.
- ID
- ZDB-PUB-190830-10
- Date
- 2019
- Source
- Circulation. Genomic and precision medicine 12(9): 397-406 (Journal)
- Registered Authors
- Hassel, David, van der Linde, Herma, van Ham, Tjakko
- Keywords
- endoplasmic reticulum, membrane proteins, pediatric, tail-anchoring
- MeSH Terms
-
- Alleles
- Amino Acid Sequence
- Animals
- Arsenite Transporting ATPases/chemistry
- Arsenite Transporting ATPases/genetics*
- Arsenite Transporting ATPases/metabolism
- Cardiomyopathies/enzymology
- Cardiomyopathies/genetics*
- Child, Preschool
- Cytosol/enzymology*
- Disease Models, Animal
- Exome
- Female
- Genetic Variation
- Humans
- Point Mutation*
- Protein Transport
- Sequence Alignment
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 31461301 Full text @ Circ Genom Precis Med
Citation
Verhagen, J.M.A., van den Born, M., van der Linde, H.C., Nikkels, P.G.J., Verdijk, R.M., Kivlen, M.H., van Unen, L.M.A., Baas, A.F., Ter Heide, H., van Osch-Gevers, L., Hoogeveen-Westerveld, M., Herkert, J.C., Bertoli-Avella, A.M., van Slegtenhorst, M.A., Wessels, M.W., Verheijen, F.W., Hassel, D., Hofstra, R.M.W., Hegde, R.S., van Hasselt, P.M., van Ham, T.J., van de Laar, I.M.B.H. (2019) Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy. Circulation. Genomic and precision medicine. 12(9):397-406.
Abstract
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.
Errata / Notes
This article corrects ZDB-PUB-220906-207.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping