PMID- 31625562
OWN - NLM
STAT- MEDLINE
DCOM- 20200601
LR  - 20210430
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 28
IP  - 23
DP  - 2019 Dec 1
TI  - Model system identification of novel congenital heart disease gene candidates: 
      focus on RPL13.
PG  - 3954-3969
LID - 10.1093/hmg/ddz213 [doi]
AB  - Genetics is a significant factor contributing to congenital heart disease (CHD), 
      but our understanding of the genetic players and networks involved in CHD 
      pathogenesis is limited. Here, we searched for de novo copy number variations 
      (CNVs) in a cohort of 167 CHD patients to identify DNA segments containing 
      potential pathogenic genes. Our search focused on new candidate disease genes 
      within 19 deleted de novo CNVs, which did not cover known CHD genes. For this 
      study, we developed an integrated high-throughput phenotypical platform to probe 
      for defects in cardiogenesis and cardiac output in human induced pluripotent stem 
      cell (iPSC)-derived multipotent cardiac progenitor (MCPs) cells and, in parallel, 
      in the Drosophila in vivo heart model. Notably, knockdown (KD) in MCPs of RPL13, 
      a ribosomal gene and SON, an RNA splicing cofactor, reduced proliferation and 
      differentiation of cardiomyocytes, while increasing fibroblasts. In the fly, 
      heart-specific RpL13 KD, predominantly at embryonic stages, resulted in a 
      striking 'no heart' phenotype. KD of Son and Pdss2, among others, caused 
      structural and functional defects, including reduced or abolished contractility, 
      respectively. In summary, using a combination of human genetics and cardiac model 
      systems, we identified new genes as candidates for causing human CHD, with 
      particular emphasis on ribosomal genes, such as RPL13. This powerful, novel 
      approach of combining cardiac phenotyping in human MCPs and in the in vivo 
      Drosophila heart at high throughput will allow for testing large numbers of CHD 
      candidates, based on patient genomic data, and for building upon existing genetic 
      networks involved in heart development and disease.
CI  - (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Schroeder, Analyne M
AU  - Schroeder AM
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Allahyari, Massoud
AU  - Allahyari M
AD  - Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA.
FAU - Vogler, Georg
AU  - Vogler G
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Missinato, Maria A
AU  - Missinato MA
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Nielsen, Tanja
AU  - Nielsen T
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Yu, Michael S
AU  - Yu MS
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Theis, Jeanne L
AU  - Theis JL
AD  - Division of Pediatric Cardiology, Department of Pediatric and Adolescent 
      Medicine, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Larsen, Lars A
AU  - Larsen LA
AD  - Department of Cellular and Molecular Medicine, University of Copenhagen, 
      Copenhagen, Denmark.
FAU - Goyal, Preeya
AU  - Goyal P
AD  - Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
FAU - Rosenfeld, Jill A
AU  - Rosenfeld JA
AD  - Baylor College of Medicine, Houston, TX, USA.
FAU - Nelson, Timothy J
AU  - Nelson TJ
AD  - Division of Pediatric Cardiology, Department of Pediatric and Adolescent 
      Medicine, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Olson, Timothy M
AU  - Olson TM
AD  - Division of Pediatric Cardiology, Department of Pediatric and Adolescent 
      Medicine, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Colas, Alexandre R
AU  - Colas AR
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Grossfeld, Paul
AU  - Grossfeld P
AD  - Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA.
FAU - Bodmer, Rolf
AU  - Bodmer R
AD  - Development, Aging and Regeneration Program, Sanford-Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
LA  - eng
GR  - R01 HL054732/HL/NHLBI NIH HHS/United States
GR  - R01 HL148827/HL/NHLBI NIH HHS/United States
GR  - F32 HL131425/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RPL13 protein, human)
RN  - 0 (Ribosomal Proteins)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cohort Studies
MH  - *DNA Copy Number Variations
MH  - Disease Models, Animal
MH  - Drosophila
MH  - Female
MH  - Gene Regulatory Networks
MH  - Heart Defects, Congenital/*genetics
MH  - Humans
MH  - Induced Pluripotent Stem Cells/chemistry/cytology/pathology
MH  - Male
MH  - Myocardium/*cytology/metabolism/pathology
MH  - Myocytes, Cardiac/chemistry/cytology/pathology
MH  - Neoplasm Proteins/*genetics
MH  - Retrospective Studies
MH  - Ribosomal Proteins/*genetics
PMC - PMC7202142
EDAT- 2019/10/19 06:00
MHDA- 2020/06/02 06:00
PMCR- 2020/12/01
CRDT- 2019/10/19 06:00
PHST- 2019/05/02 00:00 [received]
PHST- 2019/05/28 00:00 [revised]
PHST- 2019/06/21 00:00 [accepted]
PHST- 2019/10/19 06:00 [pubmed]
PHST- 2020/06/02 06:00 [medline]
PHST- 2019/10/19 06:00 [entrez]
PHST- 2020/12/01 00:00 [pmc-release]
AID - 5589181 [pii]
AID - ddz213 [pii]
AID - 10.1093/hmg/ddz213 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2019 Dec 1;28(23):3954-3969. doi: 10.1093/hmg/ddz213.