Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Clin Invest. 2009 Sep;119(9):2737-44. doi: 10.1172/JCI38292. Epub 2009 Aug 24.

Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.

Author information

  • 1Institut für Neurale Signalverarbeitung, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.

Abstract

Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G-->A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.

Comment in

PMID:
19726882
[PubMed - indexed for MEDLINE]
PMCID:
PMC2735920
Free PMC Article

Images from this publication.See all images (6)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Journal of Clinical Investigation Icon for PubMed Central Icon for Faculty of 1000
    Loading ...
    Write to the Help Desk