PMID- 10086971
OWN - NLM
STAT- MEDLINE
DCOM- 19990414
LR  - 20220310
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 99
IP  - 11
DP  - 1999 Mar 23
TI  - C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated
      mutation in cardiac event occurrence.
PG  - 1464-70
AB  - BACKGROUND: The long-QT syndrome (LQTS) is a genetically heterogeneous disease in
      which 4 genes encoding ion-channel subunits have been identified. Most of the
      mutations have been determined in the transmembrane domains of the cardiac
      potassium channel genes KCNQ1 and HERG. In this study, we investigated the 3'
      part of HERG for mutations. METHODS AND RESULTS: New specific primers allowed the
      amplification of the 3' part of HERG, the identification of 2 missense mutations,
      S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp
      insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in
      2 of the probands of these families. Lastly, in a large family, a maternally
      inherited G to A transition was found in the splicing donor consensus site of
      HERG, 2592+1G-A, and a paternally inherited mutation, A341E, was identified in
      KCNQ1. The 2 more severely affected sisters bore both mutations. CONCLUSIONS: The
      discovery of mutations in the C-terminal part of HERG emphasizes that this region
      plays a significant role in cardiac repolarization. Clinical data suggests that
      these mutations may be less malignant than mutations occurring in the pore
      region, but they can become clinically significant in cases of hypokalemia. The
      first description of 2 patients with double heterozygosity associated with a
      dramatic malignant phenotype implies that genetic analysis of severely affected
      young patients should include an investigation for >1 mutation in the LQT genes.
FAU - Berthet, M
AU  - Berthet M
AD  - INSERM U153, Service de Biochimie, Groupe Hospitalier Pitie-Salpetriere, Paris;
      Service de Cardiologie, Hopital Lariboisiere, Paris, France.
FAU - Denjoy, I
AU  - Denjoy I
FAU - Donger, C
AU  - Donger C
FAU - Demay, L
AU  - Demay L
FAU - Hammoude, H
AU  - Hammoude H
FAU - Klug, D
AU  - Klug D
FAU - Schulze-Bahr, E
AU  - Schulze-Bahr E
FAU - Richard, P
AU  - Richard P
FAU - Funke, H
AU  - Funke H
FAU - Schwartz, K
AU  - Schwartz K
FAU - Coumel, P
AU  - Coumel P
FAU - Hainque, B
AU  - Hainque B
FAU - Guicheney, P
AU  - Guicheney P
LA  - eng
PT  - Case Reports
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Cation Transport Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (ERG protein, human)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (KCNH6 protein, human)
RN  - 0 (KCNQ Potassium Channels)
RN  - 0 (KCNQ1 Potassium Channel)
RN  - 0 (KCNQ1 protein, human)
RN  - 0 (Kcnq1 protein, mouse)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcriptional Regulator ERG)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - *Cation Transport Proteins
MH  - Cattle
MH  - Child, Preschool
MH  - Consensus Sequence
MH  - DNA Mutational Analysis
MH  - *DNA-Binding Proteins
MH  - ERG1 Potassium Channel
MH  - Ether-A-Go-Go Potassium Channels
MH  - Heart/physiopathology
MH  - Humans
MH  - Hypokalemia/*complications/physiopathology
MH  - Ion Transport
MH  - KCNQ Potassium Channels
MH  - KCNQ1 Potassium Channel
MH  - Long QT Syndrome/complications/*genetics/physiopathology
MH  - Male
MH  - Membrane Potentials
MH  - Mice
MH  - Middle Aged
MH  - Molecular Sequence Data
MH  - Myocardium/metabolism
MH  - Pedigree
MH  - *Point Mutation
MH  - Polymorphism, Single-Stranded Conformational
MH  - Potassium Channels/*genetics
MH  - *Potassium Channels, Voltage-Gated
MH  - RNA Splicing
MH  - Sequence Alignment
MH  - Torsades de Pointes/etiology/*genetics/physiopathology
MH  - *Trans-Activators
MH  - Transcriptional Regulator ERG
EDAT- 1999/03/23 00:00
MHDA- 1999/03/23 00:01
CRDT- 1999/03/23 00:00
PHST- 1999/03/23 00:00 [pubmed]
PHST- 1999/03/23 00:01 [medline]
PHST- 1999/03/23 00:00 [entrez]
AID - 10.1161/01.cir.99.11.1464 [doi]
PST - ppublish
SO  - Circulation. 1999 Mar 23;99(11):1464-70. doi: 10.1161/01.cir.99.11.1464.