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PMID: 19726882 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 119 ·No. 9 ·2009-09-00 ·Pages 2737-44

Kruse M, Schulze-Bahr E, Corfield V, Beckmann A, Stallmeyer B, Kurtbay G, Ohmert I, Schulze-Bahr E, Brink P, Pongs O

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.

MeSH Terms
Amino Acid Sequence Amino Acid Substitution Base Sequence Bundle-Branch Block/genetics,metabolism,physiopathology Child DNA/genetics Electrocardiography Endocytosis Female Genes, Dominant Humans Male Middle Aged Molecular Sequence Data Mutation, Missense Pedigree Purkinje Fibers/metabolism RNA, Messenger/genetics,metabolism Sequence Homology, Amino Acid Small Ubiquitin-Related Modifier Proteins/metabolism South Africa TRPM Cation Channels/genetics,metabolism
Chemicals
RNA, Messenger Small Ubiquitin-Related Modifier Proteins TRPM Cation Channels TRPM4 protein, human DNA
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Kruse Martin
Institut für Neurale Signalverarbeitung, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.
Schulze-Bahr Eric
Corfield Valerie
Beckmann Alf
Stallmeyer Birgit
Kurtbay Güven
Ohmert Iris
Schulze-Bahr Ellen
Brink Paul
Pongs Olaf
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI38292
Published
2009-09-00
Epub
2009-00-24
Pages
2737-44
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2735920
Subset
IM
Corrections
CommentIn
PMID: 19726880
CommentIn
PMID: 20095982
External Links
PubMed source DOI: 10.1172/JCI38292 PMC Full Text View journal details
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