Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus Na Li, Lakshman Subrahmanyan, Emily Smith,

Slides:

Advertisements

Similar presentations

Hongda Li, Stephanie L. Bielas, Maha S

Advertisements

Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal- Recessive Intellectual Disability Muzammil Ahmad Khan, Muhammad Arshad Rafiq,

A Single SNP in an Evolutionary Conserved Region within Intron 86 of the HERC2 Gene Determines Human Blue-Brown Eye Color Richard A. Sturm, David L.

Michael Dannemann, Janet Kelso The American Journal of Human Genetics

Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4 S. Amer Riazuddin, Shivakumar Vasanth,

Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore,

Soraya Beiraghi, Swapan K. Nath, Matthew Gaines, Desh D

Genomewide Linkage Scan Identifies a Novel Susceptibility Locus for Restless Legs Syndrome on Chromosome 9p Shenghan Chen, William G. Ondo, Shaoqi Rao,

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor Giuseppina Divisato, Daniela Formicola, Teresa Esposito, Daniela Merlotti,

Li Wang, Dong-chuan Guo, Jiumei Cao, Limin Gong, Kristine E

A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann,

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I Christian Guelly, Peng-Peng.

ADAMTS7 Cleavage and Vascular Smooth Muscle Cell Migration Is Affected by a Coronary-Artery-Disease-Associated Variant Xiangyuan Pu, Qingzhong Xiao,

Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease

A Single SNP in an Evolutionary Conserved Region within Intron 86 of the HERC2 Gene Determines Human Blue-Brown Eye Color Richard A. Sturm, David L.

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms Karin Weiss,

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Attention-Deficit/Hyperactivity Disorder in a Population Isolate: Linkage to Loci at 4q13.2, 5q33.3, 11q22, and 17p11 Mauricio Arcos-Burgos, F. Xavier.

Mutations in ABCB6 Cause Dyschromatosis Universalis Hereditaria

CNNM2, Encoding a Basolateral Protein Required for Renal Mg2+ Handling, Is Mutated in Dominant Hypomagnesemia Marchel Stuiver, Sergio Lainez, Constanze.

Michael Dannemann, Janet Kelso The American Journal of Human Genetics

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation Marielle Alders, Tamara T. Koopmann,

Volume 8, Issue 2, Pages (February 2005)

Allelic Heterogeneity at the Serotonin Transporter Locus (SLC6A4) Confers Susceptibility to Autism and Rigid-Compulsive Behaviors James S. Sutcliffe,

Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy Kornelia Neveling,

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.

IFAP Syndrome Is Caused by Deficiency in MBTPS2, an Intramembrane Zinc Metalloprotease Essential for Cholesterol Homeostasis and ER Stress Response Frank.

PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy.

An RMND1 Mutation Causes Encephalopathy Associated with Multiple Oxidative Phosphorylation Complex Deficiencies and a Mitochondrial Translation Defect

Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease Dong-Chuan.

EB3 Regulates Microtubule Dynamics at the Cell Cortex and Is Required for Myoblast Elongation and Fusion Anne Straube, Andreas Merdes Current Biology

Jungmook Lyu, Vicky Yamamoto, Wange Lu Developmental Cell

Mutations in PMFBP1 Cause Acephalic Spermatozoa Syndrome

Aicardi-Goutières Syndrome Is Caused by IFIH1 Mutations

Airong Li, Sonia Davila, Laszlo Furu, Qi Qian, Xin Tian, Patrick S

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

Local Arrangement of Fibronectin by Myofibroblasts Governs Peripheral Nuclear Positioning in Muscle Cells William Roman, João P. Martins, Edgar R. Gomes

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

Mapping of Charcot-Marie-Tooth Disease Type 1C to Chromosome 16p Identifies a Novel Locus for Demyelinating Neuropathies Valerie A. Street, Jeff D. Goldy,

Global Transcriptional Repression in C

Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome

Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture Yutaka Shimomura, Muhammad.

Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features Emma Tham, Anna Lindstrand, Avni Santani, Helena Malmgren,

Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease Michael N. Weedon, Robert Hastings,

Allelic Heterogeneity at the Serotonin Transporter Locus (SLC6A4) Confers Susceptibility to Autism and Rigid-Compulsive Behaviors James S. Sutcliffe,

Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

PEX3 Is the Causal Gene Responsible for Peroxisome Membrane Assembly–Defective Zellweger Syndrome of Complementation Group G Kamran Ghaedi, Masanori.

Nonsense Mutations in SMPX, Encoding a Protein Responsive to Physical Force, Result in X-Chromosomal Hearing Loss Antje K. Huebner, Marta Gandia, Peter.

A Defect in the TUSC3 Gene Is Associated with Autosomal Recessive Mental Retardation Masoud Garshasbi, Valeh Hadavi, Haleh Habibi, Kimia Kahrizi, Roxana.

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct (DFNB4) Tao Yang, Hilmar Vidarsson,

Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3 Abdul Noor, Christian Windpassinger, Irina Vitcu, Marija.

Volume 71, Issue 6, Pages (March 2007)

Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth

Exome Sequence Identifies RIPK4 as the Bartsocas- Papas Syndrome Locus

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng,

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan,

Akio Tanaka, Sarah Weinel, Nikoletta Nagy, Mark O'Driscoll, Joey E

Meconium Ileus Caused by Mutations in GUCY2C, Encoding the CFTR-Activating Guanylate Cyclase 2C Hila Romi, Idan Cohen, Daniella Landau, Suliman Alkrinawi,

Identification and Functional Consequences of a New Mutation (E155G) in the Gene for GCAP1 That Causes Autosomal Dominant Cone Dystrophy Susan E. Wilkie,

Epigenetic Allele Silencing Unveils Recessive RYR1 Mutations in Core Myopathies Haiyan Zhou, Martin Brockington, Heinz Jungbluth, David Monk, Philip Stanier,

Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain

Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal- Recessive Intellectual Disability Muzammil Ahmad Khan, Muhammad Arshad Rafiq,

Identification of a New Splice Form of the EDA1 Gene Permits Detection of Nearly All X- Linked Hypohidrotic Ectodermal Dysplasia Mutations Alex W. Monreal,

Identification and Functional Analysis of ZIC3 Mutations in Heterotaxy and Related Congenital Heart Defects Stephanie M. Ware, Jianlan Peng, Lirong Zhu,

Presentation transcript:

Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus Na Li, Lakshman Subrahmanyan, Emily Smith, Xiaoqing Yu, Samir Zaidi, Murim Choi, Shrikant Mane, Carol Nelson-Williams, Mohaddeseh Behjati, Mohammad Kazemi, Mohammad Hashemi, Mohsen Fathzadeh, Anand Narayanan, Likun Tian, Farhad Montazeri, Mitra Mani, Michael L. Begleiter, Brian G. Coon, Henry T. Lynch, Eric N. Olson, Hongyu Zhao, Jürgen Ruland, Richard P. Lifton, Arya Mani The American Journal of Human Genetics Volume 98, Issue 6, Pages 1082-1091 (June 2016) DOI: 10.1016/j.ajhg.2016.03.022 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 PRDM6 p.Arg549Gln in a Large PDA-Affected Kindred (A) Pedigree PDA-101 is shown. Individuals with PDA are indicated by black symbols, individuals without PDA are shown as unfilled symbols, and individuals with unknown PDA status are shown with partially filled squares. Circles represent females, squares represent males, and symbols with a slash through them indicate deceased subjects. Haplotypes on 5q23 are shown under each individual. (B) Multipoint LOD scores for linkage of PDA to 5q23. SNPs tightly linked to the location of PRDM6 in the LOD-1 region are shown. The maximum LOD score is indicated, and the location of PRDM6 is shown. The LOD score peak occurs at θ = 0 with marker rs2081914, and the LOD-1 interval spans 10 cM. (C) The DNA sequence of a segment flanking c.1646G>A in PRDM6 is shown from an unaffected kindred member (left) and a heterozygous mutation carrier (right). This single-base substitution (asterisk) changes the wild-type arginine to glutamine at amino acid 549 (p.Arg549Gln). (D) A portion of the PRDM6 amino acid sequence flanking Arg549 is shown from diverse vertebrate species. The American Journal of Human Genetics 2016 98, 1082-1091DOI: (10.1016/j.ajhg.2016.03.022) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Independent Non-conservative Mutations of PRDM6 in Subjects with PDA (A and B) A pedigree with a DNA segment flanking the PRDM6 c.788G>C mutation (resulting in p.Cys263Ser) and a portion of the protein flanking Cys263 in diverse vertebrate species are shown in (A). A pedigree with a DNA segment flanking the PRDM6 c.1385A>G mutation (resulting in p.Arg549Gln) and a portion of the protein flanking Gln462 in diverse vertebrate species are shown in (B). Individuals with PDA are indicated by black symbols, individuals without PDA are shown as unfilled symbols, and individuals with unknown PDA status are shown with partially filled squares. Circles represent females, squares represent males, and symbols with a slash through them indicate deceased subjects. (C) A schematic of PRDM6 with functional domains and the location of the three independent mutations are shown. Intronic regions are not drawn to scale. ZF denotes zinc finger. The American Journal of Human Genetics 2016 98, 1082-1091DOI: (10.1016/j.ajhg.2016.03.022) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 The Effect of PRDM6 Amino Acid Substitutions on Its Nuclear Localization Immunofluorescence staining of wild-type PRDM6, PRDM6 p.Arg549Gln (p.R549Q), and p.Cys263Ser (p.C263S) in HEK293 cells. Whereas wild-type PRDM6 and p.Cys263Ser were localized in the nucleus, p.Arg549Gln was predominantly localized in the cytoplasm. Colors are as follows: blue, DAPI; green, phalloidin; and red, PRDM6 with FLAG tag. Scale bars represent 7 μm. The American Journal of Human Genetics 2016 98, 1082-1091DOI: (10.1016/j.ajhg.2016.03.022) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 The Effect of PRDM6 Amino Acid Substitutions on MYH11 Cellular Levels Immunostaining demonstrates the localization of PRDM6 (red) in relationship to the nucleus (blue) and the staining for MYH11 in human aortic smooth muscle cells. Cells infected with wild-type PRDM6, PRDM6 p.Arg549Gln (p.R549Q), and PRDM6 p.Cys263Ser (p.C263S) are shown in the top, middle, and bottom rows, respectively. Wild-type PRDM6 suppressed MYH11. Substitution p.Arg549Gln was largely retained in the cytoplasm, whereas p.Cys263Ser was mainly expressed in the nucleus. In smooth muscle cells overexpressing DNA encoding p.Arg549Gln and p.Cys263Ser, MYH11 staining was comparable to that in non-transfected cells. Dotted lines delineate transfected cells. Scale bars represent 28 μm. The American Journal of Human Genetics 2016 98, 1082-1091DOI: (10.1016/j.ajhg.2016.03.022) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 5 The Effect of PRDM6 Amino Acid Substitutions on the Amounts of H4K20me2, H3K9me2, MYH11, and α-SMA Immunoblot shows the amounts of histones H4K20me2 and H3K9me2 (A) and MYH11 and α-SMA (B) in wild-type human aortic VSMCs transfected with wild-type PRDM6, PRDM6 p.Arg549Gln (p.R549Q), and PRDM6 p.Cys263Ser (p.C263S). Cells transfected with empty vector were used as controls. The lower panel shows the relative intensities by densitometry. Error bars denote the SEM. The American Journal of Human Genetics 2016 98, 1082-1091DOI: (10.1016/j.ajhg.2016.03.022) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 6 Dynamic Changes in PRDM6 Abundance in Mouse DA and Great Vessels (A) H&E staining of the aorta (AO), ductus arteriosus (DA), and pulmonary artery (PA) at E14.5, E17.5, and P0.5. (B and C) IF staining of PRDM6, α-SMA, and CD31 at E14.5, E17.5, and P0.5. (B) PRDM6 was detectable in smooth muscle cells, but not in endothelia cells, of the DA at E14.15 and E17.5. Its amounts were diminished in the DA at P0.5. (C) PRDM6 was persistently detected in smooth muscle cells of the aorta at all three embryonic stages without significant variation. Scale bars represent 37 μm. (D and E) Relative intensities of PRDM6 in the DA (D) and aorta (E) at E14.5, E17.5, and P0.5 in seven mice. L denotes lumen. Arrowheads point toward PRDM6 staining. Error bars denote the SEM. The American Journal of Human Genetics 2016 98, 1082-1091DOI: (10.1016/j.ajhg.2016.03.022) Copyright © 2016 American Society of Human Genetics Terms and Conditions