PMID- 37404133
OWN - NLM
STAT- MEDLINE
DCOM- 20230724
LR  - 20230803
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 12
DP  - 2023 Jul 5
TI  - Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, 
      maintain cardiac contractility and actomyosin integrity.
LID - 10.7554/eLife.83385 [doi]
LID - e83385
AB  - 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 performed 
      whole genome sequencing (WGS) on 183 HLHS patient-parent trios to identify 
      candidate genes, which were functionally tested in the Drosophila heart model. 
      Bioinformatic analysis of WGS data from an index family of a HLHS proband born to 
      consanguineous parents prioritized 9 candidate genes with rare, predicted 
      damaging homozygous variants. Of them, cardiac-specific knockdown (KD) of 
      mitochondrial MICOS complex subunit dCHCHD3/6 resulted in drastically compromised 
      heart contractility, diminished levels of sarcomeric actin and myosin, reduced 
      cardiac ATP levels, and mitochondrial fission-fusion defects. These 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 assembly. Five additional HLHS probands harbored rare, 
      predicted damaging variants in CHCHD3 or CHCHD6. Hypothesizing an oligogenic 
      basis for HLHS, we tested 60 additional prioritized candidate genes from these 
      patients 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, E3 ubiquitin ligase), or SPTBN1 (beta-Spectrin, scaffolding 
      protein) caused synergistic heart defects, suggesting the likely involvement of 
      diverse 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.
CI  - (c) 2023, Birker, Ge, Kirkland et al.
FAU - Birker, Katja
AU  - Birker K
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Ge, Shuchao
AU  - Ge S
AUID- ORCID: 0000-0002-6590-9050
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Kirkland, Natalie J
AU  - Kirkland NJ
AD  - Department of Bioengineering, Sanford Consortium for Regenerative Medicine, UCSD, 
      School of Medicine, San Diego, United States.
FAU - Theis, Jeanne L
AU  - Theis JL
AUID- ORCID: 0000-0002-4494-8683
AD  - Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, United 
      States.
FAU - Marchant, James
AU  - Marchant J
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Fogarty, Zachary C
AU  - Fogarty ZC
AUID- ORCID: 0000-0001-5588-3216
AD  - Division of Computational Biology, Department of Quantitative Health Sciences, 
      Mayo Clinic, Rochester, United States.
FAU - Missinato, Maria A
AU  - Missinato MA
AUID- ORCID: 0000-0001-9055-758X
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Kalvakuri, Sreehari
AU  - Kalvakuri S
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Grossfeld, Paul
AU  - Grossfeld P
AD  - Department of Pediatrics, UCSD School of Medicine, La Jolla, Rady's Hospital MC 
      5004, San Diego, United States.
FAU - Engler, Adam J
AU  - Engler AJ
AD  - Department of Bioengineering, Sanford Consortium for Regenerative Medicine, UCSD, 
      School of Medicine, San Diego, United States.
FAU - Ocorr, Karen
AU  - Ocorr K
AUID- ORCID: 0000-0003-2593-0119
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Nelson, Timothy J
AU  - Nelson TJ
AUID- ORCID: 0000-0002-3862-7023
AD  - Center for Regenerative Medicine, Division of Pediatric Cardiology, Department of 
      Pediatric and Adolescent Medicine, Division of General Internal Medicine, 
      Department of Molecular and Pharmacology and Experimental Therapeutics, Mayo 
      Clinic, Rochester, United States.
FAU - Colas, Alexandre R
AU  - Colas AR
AUID- ORCID: 0000-0001-8489-0570
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Olson, Timothy M
AU  - Olson TM
AUID- ORCID: 0000-0003-2716-9423
AD  - Department of Cardiovascular Medicine, Division of Pediatric Cardiology, 
      Department of Pediatric & Adolescent Medicine, Cardiovascular Genetics Research 
      Laboratory, Mayo Clinic, Rochester, United States.
FAU - Vogler, Georg
AU  - Vogler G
AUID- ORCID: 0000-0002-8303-3531
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
FAU - Bodmer, Rolf
AU  - Bodmer R
AUID- ORCID: 0000-0001-9087-1210
AD  - Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging 
      Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United 
      States.
LA  - eng
SI  - Dryad/10.5061/dryad.z8w9ghxj1
GR  - R01 HL153645/HL/NHLBI NIH HHS/United States
GR  - R01 HL054732/HL/NHLBI NIH HHS/United States
GR  - P30 CA030199/CA/NCI NIH HHS/United States
GR  - R01 AG071464/AG/NIA NIH HHS/United States
GR  - R01 HL148827/HL/NHLBI NIH HHS/United States
GR  - R01 HL149992/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230705
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 9013-26-7 (Actomyosin)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 0 (CHCHD3 protein, human)
RN  - 0 (Mitochondrial Proteins)
SB  - IM
UOF - doi: 10.1101/2022.06.13.22276366
MH  - Humans
MH  - *Hypoplastic Left Heart Syndrome/genetics
MH  - Actomyosin
MH  - *Heart Defects, Congenital
MH  - Computational Biology
MH  - Adenosine Triphosphate
MH  - Mitochondrial Proteins
PMC - PMC10361721
OTO - NOTNLM
OT  - CHCHD3/6
OT  - CHD
OT  - D. melanogaster
OT  - Drosophila
OT  - HLHS
OT  - MICOS
OT  - genetics
OT  - genomics
OT  - human
COIS- KB, SG, NK, JT, JM, ZF, MM, SK, PG, AE, KO, TN, AC, TO, GV, RB No competing 
      interests declared
EDAT- 2023/07/05 13:05
MHDA- 2023/07/24 06:41
PMCR- 2023/07/05
CRDT- 2023/07/05 09:54
PHST- 2022/09/14 00:00 [received]
PHST- 2023/07/04 00:00 [accepted]
PHST- 2023/07/24 06:41 [medline]
PHST- 2023/07/05 13:05 [pubmed]
PHST- 2023/07/05 09:54 [entrez]
PHST- 2023/07/05 00:00 [pmc-release]
AID - 83385 [pii]
AID - 10.7554/eLife.83385 [doi]
PST - epublish
SO  - Elife. 2023 Jul 5;12:e83385. doi: 10.7554/eLife.83385.