of the Max - MDC

Heart Diseases
Coordinator: Ludwig Thierfelder
Cardiovascular Molecular
Genetics
Ludwig Thierfelder
Genetics of heart muscle disorders, regeneration of the embryonic heart and vascular genetics/pathophysiology
are major topics of the group. New disease genes/mutations and disease loci associated with
dilated, arrhythmogenic, and other forms of cardiomyopathies have been identified and our analysis of
Pseudoxanthoma elasticum mutations have been extentend. We have demonstrated the capacity of the
embryonic heart to regenerate from inactivation of X-linked hccs coding for an enzyme which is responsible
for activation of cytochromes c and c1 within the mitochondrial electron transport chain. In another set of
experiments we showed that liver X receptor agonists which are potential targets for the treatment of
metabolic, inflammatory and cardiovascular diseases negatively interfere with cytokine-induced nuclear
receptor corepressor dissociation from the C-reactive protein promoter, thus maintaining this gene in a
repressed state.
Genetics of heart muscle disorders
Sabine Klaassen, Susanne Probst
Autosomal dominant dilated cardiomyopathy (DCM) is a
genetically and phenotypically heterogenous condition. In
two large kindreds DCM was found to be associated with
early onset of disease, sudden cardiac death and diffuse
myocardial fibrosis. In a genome wide screen we have identified
a new locus on chromosome 10q25-q26 and currently
search for the disease causing mutation. Arrhythmogenic
right ventricular cardiomyopathy (ARVC) is a often difficultto-diagnose
structural cardiac disorder associated with sudden
cardiac death and heart failure. In a large cohort of 120
ARVC patients we have identified mutations in plakophilin-2
(PKP2), a component of the cardiac desmosome, in more
than 25% of cases. The great majority of PKP2 mutations in
ARVC predict protein truncations. ARVC in patients with
PKP2 mutations show a wide range of disease onset and a
reduced penetrance. Isolated non-compaction of the left
ventricle (INVC) is another rare disorder characterized by
wide intertrabecular spaces due to an arrest of endomyocardial
morphogenesis. We studied a large population of adult
INVC patients to assess whether genetic defects can also be
accounted for in this population. In one large pedigree,
INVC segregated as an autosomal dominant trait and a new
locus on chromosome 11p15 was identified in a genome
wide linkage analysis.
Molecular Genetics of Pseudoxanthoma
elasticum (PXE)
Berthold Struk
Pseudoxanthoma elasticum is a heritable systemic disorder
of the elastic tissue characterized by degenerative calcification
with subsequent disintegration and destruction of the
elastic tissue of several organs. Cardiovascular disease
encompasses a wide clinical spectrum from mental fatigue
syndrome to early cardiovascular death due to myocardial
infarction or, very rarely, gastrointestinal hemorrhage. We
have previously mapped the PXE locus to a 500 kb interval
on chromosome 16p13.1. and have shown that mutations in
a transmembrane transporter protein, ABC-C6 (also known
as MRP-6), cause PXE. Recently, an extensive mutation
screen of 81 PXE families revealed 59 distinct ABC-C6 mutations.
The types of mutations indicate loss-of-function as
the genetic mechanism for the PXE phenotype. In 76 of the
Cardiovascular and Metabolic Disease Research 27