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
-
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.
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.
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.
Metrics
-
- 1,290
- views
-
- 191
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Genetics and Genomics
- Neuroscience
The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light–12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.
-
- Evolutionary Biology
- Genetics and Genomics
Cattle (Bos taurus) play an important role in the life of humans in the Iberian Peninsula not just as a food source but also in cultural events. When domestic cattle were first introduced to Iberia, wild aurochs (Bos primigenius) were still present, leaving ample opportunity for mating (whether intended by farmers or not). Using a temporal bioarchaeological dataset covering eight millennia, we trace gene flow between the two groups. Our results show frequent hybridisation during the Neolithic and Chalcolithic, likely reflecting a mix of hunting and herding or relatively unmanaged herds, with mostly male aurochs and female domestic cattle involved. This is supported by isotopic evidence consistent with ecological niche sharing, with only a few domestic cattle possibly being managed. The proportion of aurochs ancestry in domestic cattle remains relatively constant from about 4000 years ago, probably due to herd management and selection against first generation hybrids, coinciding with other cultural transitions. The constant level of wild ancestry (~20%) continues into modern Western European breeds including Iberian cattle selected for aggressiveness and fighting ability. This study illuminates the genomic impact of human actions and wild introgression in the establishment of cattle as one of the most important domestic species today.
