The clinical variability in patients with inherited cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is harmless in a direct family member. Dosis is directed at understanding the path a mutation needs to travel to become toxic and at testing novel therapeutic approaches in experimental model systems.

Hypothesis

The clinical variability in cardiomyopathy is determined by (1) interplay between (epi)genetic and ageing-induced environmental factors (burden); (2) status of the PQC system (coping mechanisms); (3) dose and location of the mutation.

Aim of DOSIS

  1. Identify (epi)genetic modifiers influencing the CM phenotype in individuals carrying a sarcomeric mutation.
  2. Elucidate derailment of the PQC system as determinant of cellular toxicity in CM.
  3. Establish the toxic effect of mutants with respect to protein dose and mutation location.
  4. Obtain proof of concept for age-dependent secondary disease-modifiers as key players in protein toxicity of CM mutations and test novel pharmacological interventions.

Even though the gene mutation is present at birth, cardiomyopathy onset typically occurs during adulthood. Moreover, a mutation can cause cardiomyopathy in one individual, while the identical mutation is harmless in a sibling. The age/gene-related penetrance and the large clinical variability in disease-severity imply that the path a mutation has to travel in order to become toxic and injure the heart contains crossroads. To date, we do not understand these crossroads. Dosis is aimed at filling this gap. Thereto we will study why the exact same mutation causes disease in one sibling, but not in the other and how different mutations within one gene give rise to such heterogeneous clinical phenotypes. These research lines are embedded in 4 work packages, which together will elucidate the factors that determine the age of onset and severity of cardiomyopathy.

4 Work Packages

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