My laboratory while at Baylor College of Medicine had access to the DNA
of a family in Newfoundland having several affected members with arrhythmogenic
right ventricular dysplasia (ARVD). In 1998, we were successful in mapping a
locus responsible for the disease in this family located on chromosome 3p23.
This indicated the mutant gene responsible for the disease is somewhere in this
region. Unfortunately, the region was large, spanning more than 14
centimorgans, which is an area of DNA of more than 14 million bases. To narrow
the region would require having other family members with chromosomal
crossover. Because of the limited number of affecteds, we were unable to narrow
the DNA region.
ARVD is a dreaded disease in large part because of the incidence of
sudden cardiac death, which may occur in someone with minimal symptoms. The
characteristic pathological feature is fibrofatty replacement of cardiomyocytes
in the right ventricle with subsequent spread to the left ventricle. It is
inherited in an autosomal dominant pattern, although a rare form of this
disease is inherited in an autosomal recessive pattern. It is one of the most
difficult cardiomyopathies to diagnose, even in its advanced state. This is, in
large part, due to its primary involvement in the right ventricle. Diagnostic
methods such as radionuclide imaging, contrast angiograms and MRI are not
specific in detecting functional and structural abnormalities of the right
ventricle. Unlike the left ventricle, it is a low pressure system, thin walled,
and does not have an easily described consistent functional or structural
pattern. The clinical features of ARVD include ventricular ectopy, ventricular
tachycardia, HF and sudden death. The ECG may show right ventricular etopic
beats, T-wave inversion or epsilon waves. Usually, however, the ECG is either
normal or non-specific. The diagnosis is usually made on the basis of criteria
involving several clinical features as recommended by the McKenna
classification; even then there often remains some doubt.
In the study by Merner and colleagues, the investigators collected 14
additional families from Newfoundland and showed all of them mapped to the same
chromosomal region 3-p region as the original family of 1998. This is by far
the largest collection of ARVD due to a single mutant gene and has been
extensively and elegantly studied over decades. The total of 15 families
involved 496 individuals, of which DNA was available on 295. Of this 295, 83
were clinically affected with ARVD. The investigators made use of chromosomal
crossovers to narrow the DNA region of 3 from 14 centimorgans to 2.6
centimorgans. The latter region contained 20 annotated genes. The
investigators, through cloning and sequencing, identified a single missense
mutation in the transmembrane TEME43 gene responsible for the disease in all 15
families. The mutation substituted a T for C at nucleotide position 1,073. This
gene encodes for the TMEM43 protein. In the protein, the mutation leads to a
substitution of Serine for Leucine at amino acid position 350. The function of
TMEM43 remains unknown. It is present in the heart and spans the membrane with
several intramembrane domains (see Image).
Histological section of right ventricular myocardium showing fibrofatty
replacement of myocytes. Pink represents normal myocardium, blue represents
fibers and white represents fat. This was obtained from a young adult who had
died suddenly with ARVD.
Image courtesy of: Robert Roberts,
Due to the large number of members involving 15 families and multiple
generations, the investigators obtained extensive clinical information. In the
initial 295 individuals, 144 were shown to carry the mutation. The mutation was
fully penetrant in males by age 63 and in females by age 76. The incidence of
initial clinical findings in these families were ectopy (44%); left ventricular
enlargement (27%); ventricular tachycardia (9%); a QRS of 110 ms (9%); sudden
cardiac death (2%); and HF (2%). The mean lifespan of the males was 41 years
vs. 83 years for the unaffecteds, and 71 years in females vs. 83 years in
unaffecteds. The risk of dying was 6.8 times greater in affected males vs.
affected females. The authors correctly concluded that the TMEM43 mutation
induces a lethal, fully penetrant sex-influenced autosomal disorder. There is
now 11 loci that have been mapped for ARVD and nine genes identified.
While the function of TMEM43 is unknown, it does have one relevant
feature. It contains a domain that is a response element for peroxisome
proliferator receptor alpha (PPAR α), which is a known transcription
factor that up-regulates the adipogenic pathway leading to increased
adipocytes. This could account for the increase fibrofatty tissue in the
ventricles. This is also in keeping with the suggested mechanisms for several
of the other genes responsible for ARVD. The genes that encode for the
desmosomal proteins (desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2
and plakoglobin) are all known to cause ARVD. These genes are known to down
regulate the canonical Wnt/beta/Catinin signaling pathway. Suppression of this
pathway up-regulates adipogenic transcription factors, one of which is PPAR
Since implantable cardioverter defibrillators represent one of the
treatments for preventing sudden cardiac death in ARVD, screening individuals
for the TMEM43 mutation could be helpful in selecting this treatment. Secondly,
elucidation of the function of TMEM43 may provide a most needed target for
development of the first specific therapy for this disorder.
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:
- Ahmed F. Circulation. 1998;98:2791-2795.
- Merner N. Am J Hum Genet. 2008;82:809-821.
Disclosure: Dr. Roberts reports no relevant financial