April 01, 2011
3 min read

TRPM4 causes autosomal dominant isolated cardiac conduction disease

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Isolated cardiac conduction defects are not uncommon in young and older individuals. The incidence of right bundle branch block is said to be about 0.3% in the adult population. These defects are not associated with structural defects or other diseases such as ischemic heart disease.

The progressive familial heart block found in South African families was mapped to 9q13.3, and the genetic defect responsible for the disease was identified as a missense mutation in the TRPM4 gene. Several other genes have been identified to associate with cardiac conduction defects, but all of these have been associated with other significant structural abnormalities, such as PRKG2 mutants causing Wolff Parkinson-White syndrome and glycogen storage disease, or NKX2.5, which causes atrial septal defects and atrioventricular block. Thus, the role of inheritance in isolated cardiac conduction defects remains to be defined.

Role of inheritance

Robert Roberts, MD
Robert Roberts

Liu and colleagues have identified three families (one of Lebanese and two of French origin) with isolated conduction defects consisting primarily of complete or incomplete right bundle branch block. The disease is transmitted as an autosomal dominant disorder with incomplete penetrance. Genome-wide linkage analysis was performed and each of the three families mapped to chromosome 19q13.3 region with a multipoint LOD score of 10.5.

More than 10 candidate genes in the region were sequenced, and missense mutations in the TRPM4 gene (transient receptor potential malastatin 4) were found responsible for each of the three families. In one family, a missense mutation was found in exon 11 at nucleotide position 1294 (c1294). In the protein, this mutation substitutes alanine for threonine amino acid. The two other missense proteins were found in exon 5 and exon 17, also altering the protein, with arginine substituting for tryptophan (pArg114TRP) and the other glycine for asparagine (pGly844ASP) (see Figure).

The mutations were shown to segregate only with affected members in each of the three families. None of these mutations were found in 300 chromosomes of the controls. Mutations Arg164Trip and Ala432Thr are localized to the N-terminus region of the TRPM4 protein. The third mutation (Gly844Asp) maps to a sequence connecting the second and third transmembrane loops of the protein. All of these substituted amino acids are highly conserved across vertebrates. Based on certain assumptions, the penetrance was estimated at 75% for males and 54% for females.

The transient receptor potential malastatin is a relatively new family of calcium-activated, non-selective cation channels characterized by six transmembrane loops that primarily conduct sodium and potassium. TRPM4 triggers depolarization of the cell, which in turn affects many downstream events. TRPM4 is highly expressed in the heart, pancreas, placenta, prostrate and at lower levels in organs such as the kidneys, skeletal muscle, liver, intestines and spleen. The investigator of the study showed TRPM4 is also highly expressed in the purkinje system. TRPM, similar to many channels, requires transport to the membrane surface and stabilization to be activated. It is destroyed by endocytosis. The degree of current generated is a balance between the amount of TRPM4 transferred and the amount destroyed by endocytosis. Furthermore, it has been established that TRPM channels require a postranslational modification referred to as sumoylation (small ubiquitin modifier conjugation).

Figure. Diagrammatic sketch of TRPM4 Protein within the outer membrane of the cell. TRPM is a new family of calcium activated non-selected cation channels which conduct primarily sodium and potassium. Proteins consists of amino acids with each amino acid numbered starting with the amino terminus (N-terminus) and ending in the carboxyl terminus (C-terminus). The numbers refer to the position occupied by the amino acids.

Figure courtesy of: Robert Roberts, MD

To assess function, the investigators expressed the wild and mutant forms in human embryonic kidney cells and found — somewhat surprisingly — that the mutations were associated with gain-of-function and increased membrane current. The investigators performed various studies and concluded the most likely defect due to the mutation is either trafficking of the gene to the membrane surface or removal by endocytosis. Several other mutations associated with arrhythmias, such as long QT syndrome, are caused by defects in trafficking. These mutations, however, are associated with loss of function. This is one of the first trafficking defects to be associated with gain of function. The increased current leads to increased membrane leakage of conductive ions, which disables the normal action potential propagation down the purkinje system.


In summary, three novel mutations have been identified in the TRPM4 gene, which encodes for the TRPM channel involved in normal cardiac conduction. These mutations have gain-of-function, which leads to membrane leakage and impaired cardiac conduction. This disorder, which is predominantly a right bundle branch block, is inherited as an autosomal dominant disorder with greater penetrance in males than females.

The implications of this study in our understanding of cardiac conduction and for possible treatments, remain to be ascertained. However, if it is a defect in trafficking, it is conceivable that appropriate signaling could be provided and function restored to normal. This has intrigue for current-day diagnosis and for the treatment of cardiac disorders in general.

Robert Roberts, MD, is the president and CEO of the University of Ottawa Heart Institute and director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute.

For more information:

  • Liu H. Circ Cardiovasc Genet. 2010;3:374-385.