title: Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
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.
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Subrahmanyan
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan 81746, Iran.
authors.forename: Mohaddeseh
authors.initials: M
authors.lastname: Behjati
authors.affiliation: Isfahan University of Medical Sciences, Isfahan 81746, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kazemi
authors.affiliation: Isfahan University of Medical Sciences, Isfahan 81746, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hashemi
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Fathzadeh
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Narayanan
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Likun
authors.initials: L
authors.lastname: Tian
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Montazeri
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Mitra
authors.initials: M
authors.lastname: Mani
authors.affiliation: School of Medicine, University of Missouri - Kansas City, Kansas City, MO 64108, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Begleiter
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Coon
authors.affiliation: Department of Preventative Medicine, School of Medicine, Creighton University, Omaha, NE 68131, USA.
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Institute für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich 81675, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: 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.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: 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.
authors.forename: Arya
authors.initials: A
authors.lastname: Mani
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D004374:Ductus Arteriosus, Patent / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D005455:Fluorescent Antibody Technique; D006657:Histones; D006801:Humans; D015151:Immunoblotting; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D006657:Histones; D009124:Muscle Proteins; C574688:PRDM6 protein, human; D014157:Transcription Factors