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

Slides:



Advertisements
Similar presentations
Date of download: 6/2/2016 Copyright © The American College of Cardiology. All rights reserved. From: Multifocal Ectopic Purkinje-Related Premature Contractions:
Advertisements

Volume 67, Issue 2, Pages (February 2016)
Fig. 1 (A) Average current voltage relations of peak INa in Con (n=10), nAF (n=7) and cAF (n=9) cells using protocol shown on left. (B) Average.
ABCB6 Mutations Cause Ocular Coloboma
Striking In Vivo Phenotype of a Disease-Associated Human SCN5A Mutation Producing Minimal Changes in VitroClinical Perspective by Hiroshi Watanabe, Tao.
Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT.
Volume 10, Issue 1, Pages (January 2013)
Functional Modularity of the β-Subunit of Voltage-Gated Ca2+ Channels
Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia  Piero Pingitore, PhD, Saverio Massimo.
Volume 9, Issue 7, Pages (July 2012)
Identification of a novel mutation in PLA2G6 gene in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy  Lehong Gao, Liping Li,
ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor  Giuseppina Divisato, Daniela Formicola, Teresa Esposito, Daniela Merlotti,
A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function  Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann,
Volume 9, Issue 7, Pages (July 2012)
Down-regulation of L-type calcium channels in inflamed circular smooth muscle cells of the canine colon  Xiaorong Liu, Nancy J. Rusch, Joerg Striessnig,
A Nonsense Mutation in DHTKD1 Causes Charcot-Marie-Tooth Disease Type 2 in a Large Chinese Pedigree  Wang-yang Xu, Ming-min Gu, Lian-hua Sun, Wen-ting.
A Gene for Hypotrichosis Simplex of the Scalp Maps to Chromosome 6p21
Hongli Liu, M. D. , Ph. D. , Xiaofei Xu, M. D. , Ph. D. , Ting Han, M
Exome Sequencing Reveals Mutations in TRPV3 as a Cause of Olmsted Syndrome  Zhimiao Lin, Quan Chen, Mingyang Lee, Xu Cao, Jie Zhang, Donglai Ma, Long Chen,
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,
Victor G. Romanenko, George H. Rothblat, Irena Levitan 
Molecular Mechanisms Underlying KVS-1-MPS-1 Complex Assembly
Volume 76, Issue 9, Pages (November 2009)
Volume 110, Issue 11, Pages (June 2016)
Aberrant Connexin26 Hemichannels Underlying Keratitis–Ichthyosis–Deafness Syndrome Are Potently Inhibited by Mefloquine  Noah A. Levit, Caterina Sellitto,
Unitary Conductance Variation in Kir2
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.
Volume 17, Issue 9, Pages (May 2007)
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 11, Issue 1, Pages (January 2014)
Inversa Acne (Hidradenitis Suppurativa): A Case Report and Identification of the Locus at Chromosome 1p21.1–1q25.3  Min Gao, Pei-Guang Wang, Yong Cui,
Volume 14, Issue 11, Pages (November 2017)
A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility  Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.
PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy.
Identification of a Genetic Locus for Ichthyosis Vulgaris on Chromosome 10q22.3– q24.2  Ping Liu, Qingyu Yang, Xu Wang, Aiping Feng, Tao Yang, Rong Yang,
RBPJ Mutations Identified in Two Families Affected by Adams-Oliver Syndrome  Susan J. Hassed, Graham B. Wiley, Shaofeng Wang, Ji-Yun Lee, Shibo Li, Weihong.
A Nonsense Mutation in CRYBB1 Associated with Autosomal Dominant Cataract Linked to Human Chromosome 22q  Donna S. Mackay, Olivera B. Boskovska, Harry.
International Journal of Cardiology
X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3  Hongwen.
Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria  Barbara Kloeckener-Gruissem,
ABCB6 Mutations Cause Ocular Coloboma
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.
Katie C. Bittner, Dorothy A. Hanck  Biophysical Journal 
Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility  Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang.
Volume 97, Issue 3, Pages (August 2009)
Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest  Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,
Semidominant Inheritance in Olmsted Syndrome
Katsiaryna Belaya, Sarah Finlayson, Clarke R
Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment 
A Novel Dominant Mutation in Plakoglobin Causes Arrhythmogenic Right Ventricular Cardiomyopathy  Angeliki Asimaki, Petros Syrris, Thomas Wichter, Paul.
Mutations in FEZF1 Cause Kallmann Syndrome
KCNE1 Binds to the KCNQ1 Pore to Regulate Potassium Channel Activity
Effects of Temperature on Heteromeric Kv11.1a/1b and Kv11.3 Channels
Identification of a KCNE2 Gain-of-Function Mutation in Patients with Familial Atrial Fibrillation  Yiqing Yang, Min Xia, Qingfeng Jin, Saïd Bendahhou,
Identification of a Novel Locus for Marie Unna Hereditary Hypotrichosis to a 17.5 cM Interval at 1p21.1–1q21.3  Sen Yang, Min Gao, Yong Cui, Kai-Lin Yan,
Phospholemman Modulates the Gating of Cardiac L-Type Calcium Channels
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,
Regulating the Conducting States of a Mammalian Serotonin Transporter
Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene  Ralf Giess,
Volume 53, Issue 5, Pages (May 1998)
Homozygosity Mapping and Whole-Exome Sequencing to Detect SLC45A2 and G6PC3 Mutations in a Single Patient with Oculocutaneous Albinism and Neutropenia 
Mutations in CHEK2 Associated with Prostate Cancer Risk
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.
Gain-of-Function Mutation of KIT Ligand on Melanin Synthesis Causes Familial Progressive Hyperpigmentation  Zhi-Qiang Wang, Lizhen Si, Quan Tang, Debao.
Volume 45, Issue 2, Pages (January 2005)
Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness  Pawan K. Shahi, Dalton Hermans, Divya Sinha, Simran.
Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain
Zhimiao Lin, Quan Chen, Lei Shi, Mingyang Lee, Kathrin A
Presentation transcript:

Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome Yanzong Yang, Yiqing Yang, Bo Liang, Jinqiu Liu, Jun Li, Morten Grunnet, Søren-Peter Olesen, Hanne B. Rasmussen, Patrick T. Ellinor, Lianjun Gao, Xiaoping Lin, Li Li, Lei Wang, Junjie Xiao, Yi Liu, Ying Liu, Shulong Zhang, Dandan Liang, Luying Peng, Thomas Jespersen, Yi-Han Chen  The American Journal of Human Genetics  Volume 86, Issue 6, Pages 872-880 (June 2010) DOI: 10.1016/j.ajhg.2010.04.017 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and Mapping Analysis of a Family with Congenital Long QT Syndrome Black squares and circles represent male and female affected subjects, respectively; white squares and circles represent unaffected subjects; gray symbols represent subjects with clinical status undetermined. Slashes through symbols indicate deceased individuals; the arrow denotes the proband. A vertical bar beneath a family member indicates the presence of the chromosomal segment as determined by genetic evaluation. Kir3.4 is located at 11q24.3, and the markers tested in this region of chromosome 11 are listed to the left of the pedigree, with each individual's allele (represented by numbers) for each marker shown next to the chromosome bar. The chromosomal segment originating from the mutation-carrying chromosome of the affected individual in the first generation (I-2) is represented by the black bar. The American Journal of Human Genetics 2010 86, 872-880DOI: (10.1016/j.ajhg.2010.04.017) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 The Kir3.4-Gly387Arg Mutation Is Associated with Congenital Long QT Syndrome (A and B) Representative 12-lead surface electrocardiograms from the proband, demonstrating a prolonged QT interval (A) and atrial fibrillation (B). (C) Sequencing of genomic DNA from the proband revealed a heterozygous mutation in Kir3.4. The G-to-C substitution results in the introduction of an arginine (R) instead of the normal glycine (G) at codon 387 (Gly387Arg). (D) Alignment of Kir3.4 protein sequences across species demonstrating that Gly387 is conserved throughout evolution. The American Journal of Human Genetics 2010 86, 872-880DOI: (10.1016/j.ajhg.2010.04.017) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Electrophysiological Analyses of Kir3.4-Gly387Arg Whole-cell patch clamping of HEK293 cells transiently transfected with hKir3.1/hKir3.4, hKir3.1/hKir3.4/hKir3.4-Gly387Arg, or hKir3.1/hKir3.4-Gly387Arg. Note: G387R in this figure is equivalent to Gly387Arg. (A) Representative traces. Current was recorded in response to a 1000 ms voltage ramp from −100 to +50 mV from a holding potential of 0 mV (inset at top). Symmetrical potassium ion solutions with 10 μM acetylcholine (ACh) were used. (B) Normalized average ± standard error of the mean (SEM) current density values measured at −100 mV (current was elicited by the ramp protocol described above). hKir3.1/hKir3.4: −40.96 ± 6.75 pA/pF; hKir3.1/hKir3.4/hKir3.4-Gly387Arg: −15.69 ± 0.95 pA/pF; hKir3.1/hKir3.4-Gly387Arg: −9.92 ± 1.32 pA/pF; mock-transfected cells: −6.83 ± 0.86 pA/pF. ∗p < 0.05, ∗∗∗p < 0.001 versus hKir3.1/hKir3.4. (C) Representative traces. Current was recorded during 1000 ms voltage-clamp pulses from −120 to +60 mV in 20 mV steps from a holding potential of 0 mV (inset at lower right). (D) Current-voltage relationships of hKir3.1/hKir3.4, hKir3.1/hKir3.4/hKir3.4-Gly387Arg, and hKir3.1/hKir3.4-Gly387Arg with that of mock-transfected HEK cells as control. To measure current-voltage relationships, current was elicited by the step protocol described above, and current amplitudes were measured at the end of each voltage step. Kir3.1/3.4 was significantly different from Kir3.1/Kir3.4/Kir3.4-Gly387Arg or Kir3.1/Kir3.4-Gly387Arg by two-way analysis of variance (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 versus hKir3.1/hKir3.4). Kir3.1/Kir3.4/Kir3.4-Gly387Arg was not significantly different from Kir3.1/Kir3.4-Gly387Arg. At −60 mV, the average current was −19.13 ± 2.96 pA/pF for Kir3.1/Kir3.4, −8.39 ± 1.14 pA/pF for Kir3.1/Kir3.4/Kir3.4-Gly387Arg, and −6.22 ± 0.84 pA/pF for Kir3.1/Kir3.4-Gly387Arg. The American Journal of Human Genetics 2010 86, 872-880DOI: (10.1016/j.ajhg.2010.04.017) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Cell Surface Expression of Kir3.4-Gly387Arg and Kir3.1 Western blotting of HEK293 cells transiently cotransfected with hKir3.1 and hKir3.4 or hKir3.4-Gly387Arg. Note: G387R in this figure is equivalent to Gly387Arg. (A) Representative exposures of biotinylated proteins and unbound protein fractions with the indicated antibodies (AB). For mock-transfected HEK293 cells, whole-cell lysate was loaded. Na+/K+-ATPase α1 served as a loading control to make sure that equal amounts of cell lysates were loaded onto the gel. Calnexin, which is an endoplasmic-reticulum-resident protein, served as control for selective biotinylation of plasma membrane proteins. (B) Average ± SEM values from quantification of six independent experiments. ∗p < 0.05, ∗∗p < 0.001. The American Journal of Human Genetics 2010 86, 872-880DOI: (10.1016/j.ajhg.2010.04.017) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 5 Human Atrial and Ventricular Expression of Kir3.1 and Kir3.4 (A) Western blotting of proteins extracted from tissue from the left ventricular endocardial free wall (LV) and the lateral wall of the right atrium (RA) from four patients (e.g., patient 1: LV1 and RA1). (B and C) Quantification of expression levels of Kir3.1 (B) and Kir3.4 (C) in the atria and ventricles. Average ± SEM arbitrary quantification values for atrial versus ventricular expression were as follows: Kir3.1, 237 ± 54 versus 62 ± 7; Kir3.4, 182 ± 5 versus 82 ± 4. ∗p < 0.05, ∗∗∗p < 0.01. The American Journal of Human Genetics 2010 86, 872-880DOI: (10.1016/j.ajhg.2010.04.017) Copyright © 2010 The American Society of Human Genetics Terms and Conditions