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.
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
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,
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.