Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus

Am J Hum Genet. 2016 Jun 2;98(6):1082-1091. doi: 10.1016/j.ajhg.2016.03.022.

Na Li ¹, Lakshman Subrahmanyan ¹, Emily Smith ¹, Xiaoqing Yu ², Samir Zaidi ², Murim Choi ², Shrikant Mane ², Carol Nelson-Williams ², Mohaddeseh Behjati ³, Mohammad Kazemi ⁴, Mohammad Hashemi ⁴, Mohsen Fathzadeh ¹, Anand Narayanan ¹, Likun Tian ¹, Farhad Montazeri ¹, Mitra Mani ¹, Michael L Begleiter ⁵, Brian G Coon ¹, Henry T Lynch ⁶, Eric N Olson ⁷, Hongyu Zhao ², Jürgen Ruland ⁸, Richard P Lifton ⁹, Arya Mani ¹⁰

Affiliations

1 Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
2 Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
3 Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan 81746, Iran.
4 Isfahan University of Medical Sciences, Isfahan 81746, Iran.
5 School of Medicine, University of Missouri - Kansas City, Kansas City, MO 64108, USA.
6 Department of Preventative Medicine, School of Medicine, Creighton University, Omaha, NE 68131, USA.
7 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8 Institute für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich 81675, Germany.
9 Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
10 Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: arya.mani@yale.edu.

PMID: 27181681 DOI: 10.1016/j.ajhg.2016.03.022

Abstract

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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