Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity
- Sanford Burnham Prebys Medical Discovery Institute, United States
- University of California, San Diego, United States
- Mayo Clinic, United States
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a likely oligogenic etiology, but our understanding of the genetic complexities and pathogenic mechanisms leading to HLHS is limited. We therefore performed whole genome sequencing (WGS) on a large cohort of HLHS patients and their families to identify candidate genes that were then tested in Drosophila heart model for functional and structural requirements. Bioinformatic analysis of WGS data from an index family comprised of a HLHS proband born to consanguineous parents and postulated to have a homozygous recessive disease etiology, prioritized 9 candidate genes with rare, predicted damaging homozygous variants. Of the candidate HLHS gene homologs tested, cardiac-specific knockdown (KD) of mitochondrial MICOS complex subunit Chchd3/6 resulted in drastically compromised heart contractility, diminished levels of sarcomeric actin and myosin, reduced cardiac ATP levels, and mitochondrial fission-fusion defects. Interestingly, these heart defects were similar to those inflicted by cardiac KD of ATP synthase subunits of the electron transport chain (ETC), consistent with the MICOS complex’s role in maintaining cristae morphology and ETC complex assembly. Analysis of 183 genomes of HLHS patient-parent trios revealed five additional HLHS probands with rare, predicted damaging variants in CHCHD3 or CHCHD6. Hypothesizing an oligogenic basis for HLHS, we tested 60 additional prioritized candidate genes in these cases for genetic interactions with Chchd3/6 in sensitized fly hearts. Moderate KD of Chchd3/6 in combination with Cdk12 (activator of RNA polymerase II), RNF149 (goliath, gol, E3 ubiquitin ligase), or SPTBN1 (β Spectrin, β-Spec, scaffolding protein) caused synergistic heart defects, suggesting the potential involvement of a diverse set of pathways in HLHS. Further elucidation of novel candidate genes and genetic interactions of potentially disease-contributing pathways is expected to lead to a better understanding of HLHS and other CHDs.
Data availability
Data available on Dryad: doi:10.5061/dryad.z8w9ghxj1
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Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrityDryad Digital Repository, doi:10.5061/dryad.z8w9ghxj1.
Article and author information
Author details
Funding
Foundation for the National Institutes of Health (HL054732)
- Rolf Bodmer
Todd and Karen Wanek Family Program for HLHS at Mayo Clinic (NA)
- Timothy J Nelson
American Heart Association (18PRE33960593)
- Katja Birker
American Heart Association (20POST35180048)
- Natalie J Kirkland
Foundation for the National Institutes of Health (HL153645)
- Alexandre R Colas
Foundation for the National Institutes of Health (HL148827)
- Alexandre R Colas
Foundation for the National Institutes of Health (HL149992)
- Alexandre R Colas
Foundation for the National Institutes of Health (AG071464)
- Alexandre R Colas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Caroline E Burns, Boston Children's Hospital, United States
Ethics
Human subjects: Written informed consent was obtained for the index family and an HLHS cohort, under a research protocol approved by the Mayo Clinic Institutional Review Board ("Genetic Investigations in Hypoplastic Left Heart Syndrome", IRB #11-000114). Participants consented to providing clinical health record data, sample procurement for DNA analyses, and publication of de-identified research findings.
Version history
- Preprint posted: June 16, 2022 (view preprint)
- Received: September 14, 2022
- Accepted: July 4, 2023
- Accepted Manuscript published: July 5, 2023 (version 1)
- Version of Record published: July 21, 2023 (version 2)
Copyright
© 2023, Birker et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity
eLife 12:e83385.
https://doi.org/10.7554/eLife.83385
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