PMID- 10090886
OWN - NLM
STAT- MEDLINE
DCOM- 20000405
LR  - 20200824
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 64
IP  - 4
DP  - 1999 Apr
TI  - Mutations in a dominant-negative isoform correlate with phenotype in inherited
      cardiac arrhythmias.
PG  - 1015-23
AB  - The long QT syndrome is characterized by prolonged cardiac repolarization and a
      high risk of sudden death. Mutations in the KCNQ1 gene, which encodes the cardiac
      KvLQT1 potassium ion (K+) channel, cause both the autosomal dominant Romano-Ward 
      (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome. JLN
      presents with cardiac arrhythmias and congenital deafness, and heterozygous
      carriers of JLN mutations exhibit a very mild cardiac phenotype. Despite the
      phenotypic differences between heterozygotes with RW and those with JLN
      mutations, both classes of variant protein fail to produce K+ currents in
      cultured cells. We have shown that an N-terminus-truncated KvLQT1 isoform
      endogenously expressed in the human heart exerts strong dominant-negative effects
      on the full-length KvLQT1 protein. Because RW and JLN mutations concern both
      truncated and full-length KvLQT1 isoforms, we investigated whether RW or JLN
      mutations would have different impacts on the dominant-negative properties of the
      truncated KvLQT1 splice variant. In a mammalian expression system, we found that 
      JLN, but not RW, mutations suppress the dominant-negative effects of the
      truncated KvLQT1. Thus, in JLN heterozygous carriers, the full-length KvLQT1
      protein encoded by the unaffected allele should not be subject to the negative
      influence of the mutated truncated isoform, leaving some cardiac K+ current
      available for repolarization. This is the first report of a genetic disease in
      which the impact of a mutation on a dominant-negative isoform correlates with the
      phenotype.
FAU - Mohammad-Panah, R
AU  - Mohammad-Panah R
AD  - Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moleculaires, 
      INSERM CJF96-01, Hopital Hotel-Dieu, Nantes, France.
FAU - Demolombe, S
AU  - Demolombe S
FAU - Neyroud, N
AU  - Neyroud N
FAU - Guicheney, P
AU  - Guicheney P
FAU - Kyndt, F
AU  - Kyndt F
FAU - van den Hoff, M
AU  - van den Hoff M
FAU - Baro, I
AU  - Baro I
FAU - Escande, D
AU  - Escande D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (KCNQ Potassium Channels)
RN  - 0 (KCNQ1 Potassium Channel)
RN  - 0 (KCNQ1 protein, human)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Protein Isoforms)
RN  - RWP5GA015D (Potassium)
SB  - IM
MH  - Adult
MH  - Alternative Splicing/genetics
MH  - Animals
MH  - COS Cells
MH  - Child, Preschool
MH  - Exons/genetics
MH  - Female
MH  - Gene Expression
MH  - Genes, Dominant/*genetics
MH  - Genes, Recessive/genetics
MH  - Heterozygote
MH  - Humans
MH  - KCNQ Potassium Channels
MH  - KCNQ1 Potassium Channel
MH  - Long QT Syndrome/*congenital/*genetics/metabolism
MH  - Male
MH  - Membrane Potentials
MH  - Phenotype
MH  - Potassium/metabolism
MH  - Potassium Channels/*genetics/metabolism
MH  - *Potassium Channels, Voltage-Gated
MH  - Protein Isoforms/genetics/metabolism
MH  - Sequence Deletion/*genetics
MH  - Suppression, Genetic/*genetics
MH  - Transfection
PMC - PMC1377825
EDAT- 1999/03/26 03:02
MHDA- 2001/07/04 10:01
CRDT- 1999/03/26 03:02
PHST- 1999/03/26 03:02 [pubmed]
PHST- 2001/07/04 10:01 [medline]
PHST- 1999/03/26 03:02 [entrez]
AID - AJHG981042 [pii]
AID - 10.1086/302346 [doi]
PST - ppublish
SO  - Am J Hum Genet. 1999 Apr;64(4):1015-23. doi: 10.1086/302346.