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

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 (arsA arsenite transporter, ATP-binding, homolog), 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.

CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking

“…The affected individual had a mild type 2 serum transferrin isoform pattern, indicating a possible congenital disorder of glycosylation (CDG) caused by dysfunction of the TRC pathway. In addition, in 2019 an individual with compound heterozygous variants (c.913C>T; p.(Gln305 * ), c.488T>C; p.(Val163Ala)) in GET3 was described ( 10 ). This patient presented with severe neonatal-onset cardiomyopathy leading to death at age seven weeks.…”

Genetic Mapping of Climbing and Mimicry: Two Behavioral Traits Degraded During Silkworm Domestication

“…ASNA1 encodes an ATPase targeting tail-anchored protein that is versatile and important in various biological processes. In humans, mutations in ASNA1 caused rapidly progressive pediatric cardiomyopathy ( Verhagen et al, 2019 ) and might be related to early onset Parkinson’s disease ( Kun-Rodrigues et al, 2015 ). In comparisons with other Lepidoptera species, we found a non-synonymous variation specific to the domestic silkworm.…”

Zebrafish as a tractable model of human cardiovascular disease

“…In addition to the better-characterised genes or pathways described above, functional studies in zebrafish have also identified novel roles for a diverse array of genes in cardiomyopathy e.g. Raf1, Taf1a, Asn [41][42][43] . Zebrafish DCM models have also been generated through pharmacological induction by administering the potassium channel blocker terfenadine to embryos 44 , while a zebrafish model of ACM was developed using cardiomyocyte-driven expression of a plakoglobin disease variant, resulting in cardiomegaly and thinning of atrial and ventricular walls in early-adult fish 45 .…”

“…The ability to perform targeted knockdown, create disease‐specific mutations or overexpress disease variants has made zebrafish an invaluable model to validate novel candidate genes implicated in DCM, HCM and ACM. In addition to the better‐characterized genes or pathways described above, functional studies in zebrafish have also identified novel roles for a diverse array of genes in cardiomyopathy, for example, Raf1 , Taf1a and Asn (Dhandapany et al, 2014; Long et al, 2017; Verhagen et al, 2019). Zebrafish DCM models have also been generated through pharmacological induction by administering the K + channel blocker terfenadine to embryos (Gu et al, 2017), whereas a zebrafish model of ACM was developed using cardiomyocyte‐driven expression of a plakoglobin disease variant, resulting in cardiomegaly and thinning of atrial and ventricular walls in early‐adult fish (Asimaki et al, 2014).…”