Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus

Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus Publisher Pubmed

Li N¹ ; Subrahmanyan L¹ ; Smith E¹ ; Yu X² ; Zaidi S² ; Choi M² ; Mane S² ; Nelsonwilliams C² ; Bahjati M³ ; Kazemi M⁴ ; Hashemi M⁴ ; Fathzadeh M¹ ; Narayanan A¹ ; Tian L¹ Show All Authors

Li N¹
Subrahmanyan L¹
Smith E¹
Yu X²
Zaidi S²
Choi M²
Mane S²
Nelsonwilliams C²
Bahjati M³
Kazemi M⁴
Hashemi M⁴
Fathzadeh M¹
Narayanan A¹
Tian L¹
Montazeri F¹
Mani M¹
Begleiter ML⁵
Coon BG¹
Lynch HT⁶
Olson EN⁷
Zhao H²
Ruland J⁸
Lifton RP^{1, 2}
Mani A^{1, 2}

Show Affiliations

1. Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, Howard Hughes Medical Institute, New Haven, 06520, CT, United States
2. Department of Genetics, Yale University School of Medicine, New Haven, 06520, CT, United States
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, 64108, MO, United States
6. Department of Preventative Medicine, School of Medicine, Creighton University, Omaha, 68131, NE, United States
7. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, United States
8. Institute fur Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universitat Munchen, Munich, 81675, Germany

Source: American Journal of Human Genetics Published:2016

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. © 2016 American Society of Human Genetics.

2. Screening of Congenital Heart Disease Patients Using Multiplex Ligation-Dependent Probe Amplification: Early Diagnosis of Syndromic Patients, American Journal of Medical Genetics, Part A (2012)

Experts (# of related papers)

Nizal Sarrafzadegan (1)

Style	Citing Format
MLA	Li N, et al.. "Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus." American Journal of Human Genetics, vol. 98, no. 6, 2016, pp. 1082-1091.
APA	Li N, Subrahmanyan L, Smith E, Yu X, Zaidi S, Choi M, Mane S, Nelsonwilliams C, Bahjati M, Kazemi M, Hashemi M, Fathzadeh M, Narayanan A, Tian L, Montazeri F, Mani M, Begleiter ML, Coon BG, Lynch HT, ... Mani A (2016). Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus. American Journal of Human Genetics, 98(6), 1082-1091.
Chicago	Li N, Subrahmanyan L, Smith E, Yu X, Zaidi S, Choi M, Mane S, et al.. "Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus." American Journal of Human Genetics 98, no. 6 (2016): 1082-1091.
Harvard	Li N et al. (2016) 'Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus', American Journal of Human Genetics, 98(6), pp. 1082-1091.
Vancouver	Li N, Subrahmanyan L, Smith E, Yu X, Zaidi S, Choi M, et al.. Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus. American Journal of Human Genetics. 2016;98(6):1082-1091.
BibTex	@article{ author = {Li N and Subrahmanyan L and Smith E and Yu X and Zaidi S and Choi M and Mane S and Nelsonwilliams C and Bahjati M and Kazemi M and Hashemi M and Fathzadeh M and Narayanan A and Tian L and Montazeri F and Mani M and Begleiter ML and Coon BG and Lynch HT and Olson EN and Zhao H and Ruland J and Lifton RP and Mani A}, title = {Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus}, journal = {American Journal of Human Genetics}, volume = {98}, number = {6}, pages = {1082-1091}, year = {2016} }
RIS	TY - JOUR AU - Li N AU - Subrahmanyan L AU - Smith E AU - Yu X AU - Zaidi S AU - Choi M AU - Mane S AU - Nelsonwilliams C AU - Bahjati M AU - Kazemi M AU - Hashemi M AU - Fathzadeh M AU - Narayanan A AU - Tian L AU - Montazeri F AU - Mani M AU - Begleiter ML AU - Coon BG AU - Lynch HT AU - Olson EN AU - Zhao H AU - Ruland J AU - Lifton RP AU - Mani A TI - Mutations in the Histone Modifier Prdm6 Are Associated With Isolated Nonsyndromic Patent Ductus Arteriosus JO - American Journal of Human Genetics VL - 98 IS - 6 SP - 1082 EP - 1091 PY - 2016 ER -

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