Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I
Martin Kruse ... Paul Brink, Olaf Pongs
Martin Kruse ... Paul Brink, Olaf Pongs
Published September 1, 2009
Citation Information: J Clin Invest. 2009;119(9):2737-2744. doi:10.1172/JCI38292.
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Categories: Research Article Cardiology

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

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.

Authors

Martin Kruse, Eric Schulze-Bahr, Valerie Corfield, Alf Beckmann, Birgit Stallmeyer, Güven Kurtbay, Iris Ohmert, Ellen Schulze-Bahr, Paul Brink, Olaf Pongs

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TRPM4 missense mutation in exon 1 associated with PFHBI. (A) Relati...

Figure 2

TRPM4 missense mutation in exon 1 associated with PFHBI.

(A) Relative expression of TRPM4 transcripts in different tissues of nondiseased human heart was assayed by quantitative RT-PCR. TRPM4 mRNA expression levels were normalized to the level in left ventricle. Numbers of individual probes are shown in parentheses. Each experiment was done in triplicate. (B) Electropherograms show TRPM4 WT sequence and the heterozygous sequence change c.19G→A in the DNA of PFHBI-affected individuals. (C) Partial amino acid sequence alignment of TRPM4 N terminus among different species. Gray shading shows the conserved sequence motif; red shading highlights the glutamic acid substituted by lysine in TRPM4 associated with PFHBI. Numbering refers to the human sequence. (D) Diagram of TRPM4 topology and functional domains, with 6 membrane-spanning domains (TM) flanked by N- and C-terminal cytoplasmic sequences. PFHBI, PFHBI domain; CaM, Calmodulin-binding domain; WB, Walker B ATP-binding motif; CCR, coiled-coiled region. Figure part adapted with permission from Pflügers Archiv (19).