TY - JOUR
T1 - Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus
AU - Li, Na
AU - Subrahmanyan, Lakshman
AU - Smith, Emily
AU - Yu, Xiaoqing
AU - Zaidi, Samir
AU - Choi, Murim
AU - Mane, Shrikant
AU - Nelson-Williams, Carol
AU - Bahjati, Mohadesseh
AU - Kazemi, Mohammad
AU - Hashemi, Mohammad
AU - Fathzadeh, Mohsen
AU - Narayanan, Anand
AU - Tian, Likun
AU - Montazeri, Farhad
AU - Mani, Mitra
AU - Begleiter, Michael L.
AU - Coon, Brian G.
AU - Lynch, Henry T.
AU - Olson, Eric N.
AU - Zhao, Hongyu
AU - Ruland, Jürgen
AU - Lifton, Richard P.
AU - Mani, Arya
N1 - Funding Information:
This work was supported by NIH grants (1R01HL122830 and 1R01HL122822) to A.M. and the NIH Centers for Mendelian Genomics (5U54HG006504). We would like to thank Dr. Kathleen Martin from Yale University for providing us with human aortic vascular smooth muscle cells. We also thank Dr. Sekar Kathiresan at Massachusetts General Hospital for providing us with access to his whole-exome sequencing database. The authors would like to thank the National Heart, Lung, and Blood Institute Grand Opportunity (GO) Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Womens Health Initiative Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at
Funding Information:
This work was supported by NIH grants (1R01HL122830 and 1R01HL122822) to A.M. and the NIH Centers for Mendelian Genomics (5U54HG006504). We would like to thank Dr. Kathleen Martin from Yale University for providing us with human aortic vascular smooth muscle cells. We also thank Dr. Sekar Kathiresan at Massachusetts General Hospital for providing us with access to his whole-exome sequencing database. The authors would like to thank the National Heart, Lung, and Blood Institute Grand Opportunity (GO) Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women’s Health Initiative Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about .
Publisher Copyright:
© 2016 American Society of Human Genetics.
PY - 2016/6/2
Y1 - 2016/6/2
N2 - Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
AB - Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
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U2 - 10.1016/j.ajhg.2016.03.022
DO - 10.1016/j.ajhg.2016.03.022
M3 - Article
C2 - 27181681
AN - SCOPUS:84966659455
SN - 0002-9297
VL - 98
SP - 1082
EP - 1091
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -