PMID- 17576861
OWN - NLM
STAT- MEDLINE
DCOM- 20070720
LR  - 20181201
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 116
IP  - 1
DP  - 2007 Jul 3
TI  - Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by 
      nonsense-mediated mRNA decay in human long-QT syndrome.
PG  - 17-24
AB  - BACKGROUND: Long-QT syndrome type 2 (LQT2) is caused by mutations in the human 
      ether-a-go-go-related gene (hERG). More than 30% of the LQT2 mutations result in 
      premature termination codons. Degradation of premature termination 
      codon-containing mRNA transcripts by nonsense-mediated mRNA decay is increasingly 
      recognized as a mechanism for reducing mRNA levels in a variety of human 
      diseases. However, the role of nonsense-mediated mRNA decay in LQT2 mutations has 
      not been explored. METHODS AND RESULTS: We examined the expression of hERG mRNA 
      in lymphocytes from patients carrying the R1014X mutation using a technique of 
      allele-specific transcript quantification. The R1014X mutation led to a reduced 
      level of mutant mRNA compared with that of the wild-type allele. The decrease in 
      mutant mRNA also was observed in the LQT2 nonsense mutations W1001X and R1014X 
      using hERG minigenes expressed in HEK293 cells or neonatal rat ventricular 
      myocytes. Treatment with the protein synthesis inhibitor cycloheximide or RNA 
      interference-mediated knockdown of the Upf1 protein resulted in the restoration 
      of mutant mRNA to levels comparable to that of the wild-type minigene, suggesting 
      that hERG nonsense mutations are subject to nonsense-mediated mRNA decay. 
      CONCLUSIONS: These results indicate that LQT2 nonsense mutations cause a decrease 
      in mutant mRNA levels by nonsense-mediated mRNA decay rather than production of 
      truncated proteins. Our findings suggest that the degradation of hERG mutant mRNA 
      by nonsense-mediated mRNA decay is an important mechanism in LQT2 patients with 
      nonsense or frameshift mutations.
FAU - Gong, Qiuming
AU  - Gong Q
AD  - Division of Cardiovascular Medicine, Oregon Health and Science University, 3181 
      SW Sam Jackson Park Rd, Portland, OR 97239, USA.
FAU - Zhang, Li
AU  - Zhang L
FAU - Vincent, G Michael
AU  - Vincent GM
FAU - Horne, Benjamin D
AU  - Horne BD
FAU - Zhou, Zhengfeng
AU  - Zhou Z
LA  - eng
GR  - 1UL1RRO24140-01/PHS HHS/United States
GR  - R01 HL068854-05A1/HL/NHLBI NIH HHS/United States
GR  - HL68854/HL/NHLBI NIH HHS/United States
GR  - R01 HL068854/HL/NHLBI NIH HHS/United States
GR  - UL1 RR024140/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070618
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Codon, Nonsense)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 3.6.4.13 (RNA Helicases)
RN  - EC 3.6.4.13 (UPF1 protein, human)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Animals, Newborn
MH  - Cells, Cultured/metabolism
MH  - *Codon, Nonsense
MH  - Cycloheximide/pharmacology
MH  - ERG1 Potassium Channel
MH  - Ether-A-Go-Go Potassium Channels/deficiency/*genetics
MH  - Female
MH  - Frameshift Mutation
MH  - Genes, Synthetic
MH  - Humans
MH  - Kidney
MH  - Long QT Syndrome/congenital/*genetics/metabolism
MH  - Lymphocytes/metabolism
MH  - Male
MH  - Middle Aged
MH  - Myocytes, Cardiac/metabolism
MH  - Pedigree
MH  - Point Mutation
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - RNA Helicases
MH  - RNA Interference
MH  - RNA, Messenger/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Trans-Activators/antagonists & inhibitors/genetics/physiology
MH  - Transfection
PMC - PMC2376840
MID - NIHMS44835
EDAT- 2007/06/20 09:00
MHDA- 2007/07/21 09:00
PMCR- 2008/05/12
CRDT- 2007/06/20 09:00
PHST- 2007/06/20 09:00 [pubmed]
PHST- 2007/07/21 09:00 [medline]
PHST- 2007/06/20 09:00 [entrez]
PHST- 2008/05/12 00:00 [pmc-release]
AID - CIRCULATIONAHA.107.708818 [pii]
AID - 10.1161/CIRCULATIONAHA.107.708818 [doi]
PST - ppublish
SO  - Circulation. 2007 Jul 3;116(1):17-24. doi: 10.1161/CIRCULATIONAHA.107.708818. 
      Epub 2007 Jun 18.