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April 2011
 

3. Functional Genomics of Familial Hypertrophic Cardiomyopathy

Dr. rer. nat. Lucie Carrier (Team leader)

Dr. rer. nat. Verena Behrens-Gawlick (BAT IIA / Post-doctorant)

Dr. rer. nat. Giulia Mearini (BAT IIA / Post-doctorant)

Dr. Saskia Schlossarek (BAT IIA / Post-doctorant)
 
Claudia Crocini (Master student from Florence, Italy)
Christina Gedicke (Biochemist / PhD student)

Doreen Kahajetoorians (Pharmacist / PhD student)

Markus Sauer (Medical doctoral student)
 
Birgit Geertz (MTA / Technician)
Elisabeth Krämer (MTA / Technician)
Silke Reischmann (MTA / Technician)

Description of the team, research area and previous work

Lucie Carrier is a French scientist (CNRS Director of Research) who has received a Marie Curie Excellence Grant to lead an European team at the Institute of Experimental and Clinical Pharmacology of the UKE in Hamburg between 2005 and 2009. Her team is also part of the French mixed research structure (Inserm U974-CNRS UMR7215, directed by Thomas Voit in Paris). She is involved in the genetics and pathophysiology of familial hypertrophic cardiomyopathy (HCM) for 20 years.
         HCM is a myocardial disease with the major feature of asymmetric septal hypertrophy. It is one of the most common monogenic diseases with a disease prevalence of 1:500 in young adults. It is the major cause of sudden death in the young and is associated with a significant risk of heart failure. It is an autosomal-dominant familial disease in most of the cases and involves mutations in at least 13 different genes encoding proteins of the sarcomere. The first disease gene for HCM, the beta-myosin heavy chain gene, was identified in the early 90s by the team of C. Seidman (Boston). This opened the way of genetic cardiology.
         In France, K. Schwartz and M. Komajda have initiated the genetic analyses of HCM in 1991, and L. Carrier has been involved from the beginning. A French INSERM network has been created in 1992, which has largely contributed to the discovery of the molecular causes of FHC. A panel of 297 French families with FHC has been recruited, and about 2000 blood samples have been collected. Two European networks have been created later on this project and L. Carrier has been always actively involved (the BIOMED project from 1996 to 2001 and the Eurogene Heart Failure Project-Leducq Foundation from 2000 to now). The latter one allowed recruiting 350 unrelated European families with HCM. The major discoveries were (1) identification of the CMH4 locus on chromosome 11 (Carrier et al., 1993), (2) identification of the FHC disease gene MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C; Bonne / Carrier et al., 1995), (3) determination of the complete structure and organization of the MYBPC3 gene and demonstration that most of the MYBPC3 mutations produce C-terminal truncated proteins (Carrier et al., 1997), (4) identification of 97 different mutations in 9 different HCM genes in 124 unrelated families, and evidence that 5% of the families present individuals with a complex genetic status who exhibit a more severe phenotype (Richard et al., 2003), (5) identification of a polymorphism in calmodulin III promoter that modifies the expression of FHC (Friedrich et al., 2009).
         Since the mechanisms by which MYBPC3 mutations lead to HCM was not known, a large part of our projects aims at elucidating the functional consequences of HCM mutations. The major findings were: (1) cMyBP-C is expressed exclusively in the heart during human and mouse development (Fougerousse et al, 1998), (2) human truncated cMyBP-C mutants are unstable and mis-incorporated in fetal rat cardiomyocytes (Flavigny et al., 1999), (3) recombinant human truncated cMyBP-C mutants do not interact with human beta-MHC in biosensor chips (Flavigny et al., 2003), (4) heterozygous cMyBP-C targeted mice develop asymmetric septal hypertrophy, therefore constituting the first model with the major feature of HCM (Carrier et al, 2004), (5) human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties (Keller et al., 2004), (6) cMyBP-C is required for complete relaxation in diastole (Pohlmann et al., 2007), (7) truncated cMyBP-C mutants impair the ubiquitin-proteasome system, which could contribute to the pathogenesis of HCM (Sarikas/Carrier et al., 2005), (8) Atrogin-1 degrades truncated cMyBP-C but MuRF1 down-regulates the transcription of myosin-heavy chains (Mearini et al., 2010), (9) The nonsense-mediated mRNA decay and the ubiquitin-proteasome system regulate the levels of cMyBP-C in targeted Mybpc3-knock-in mice (Vignier/Schlossarek et al., 2009; Carrier et al., 2010).

Objectives

The major objective of the Carrier team is the understanding of the molecular mechanisms by which mutations in MYBPC3 lead to the development of HCM. However, a large part of the projects also evaluate new molecular tools for HCM therapy. Our projects are the following:

  1. Screening for mutations in new genes encoding components of the cardiac sarcomere in patients with HCM, and investigation of their consequences in mouse cardiac myocytes and engineered heart tissue using adeno-associated virus (AAV). Collaboration with UKE-HEXT-AAV and O. Müller, Cardiology, Heidelberg.
  2. Evaluation of the role of several protein quality controls (ubiquitin-proteasome system, autophagy and unfolded-protein response) in cardiac homeostasis, HCM and other cardiac diseases. Collaboration with G. Bonne, Inserm U974, Paris.
  3. Evaluation of RNA-based therapies in a mouse model of HCM (Mybpc3-knock-in mice). The goal is to suppress the endogenous mutation by different strategies, such as exon skipping, exon inclusion and spliceosome-mediated RNA transplicing (in mouse cardiac myocytes, engineered mouse heart tissue and in vivo using AAV). Collaborations with Luis Garcia and Thomas Voit, Inserm U974, Paris.
  4. Development of a clinical and experimental reference center for hypertrophic cardiomyopathy in Northen Germany: recruitment of patients and relatives with HCM (plus blood sample, septal myectomy, skin biopsy), deciphering of genetic causes, analysis of the pathophysiology and development of personalized therapy concepts (via reprogramming skin fibroblasts into iPS cells and differentiation in cardiac myocytes and engineered heart tissue). Collaborations with Dr Monica Patten, Cardiology UKE, HEXT-iPS, and EU-FP7-Health-BIG-Heart network, in which biopsies are shared for complementary physiological analyses.

Material and methods

 

Current Collaborations

T. Arimura (University of Tokyo, Tokyo, Japan)
G. Bonne, B. Fraysse L. Garcia, N. Vignier and T. Voit (INSERM U974-CNRS UMR7215, Paris, France)
N. Dantuma (Karolinska Institute, Stockholm)
M. Gautel (King's College, London, UK)
J. Hill (UT Southwest Medical Center, Dallas, TX, USA)
S. Marston (Imperial's College, London, UK)
C. Patterson (UNC-CH School of Medecine, Chapel Hill, NC, USA)
C. Poggesi (University of Florence, Italy)
C. Redwood (University of Oxford, UK)
J. Robbins (Children's Hospital, Cincinnati, OH, USA)
M. Sandri (University of Padova, Italy)
J. van der Velden (VUMC, Amsterdam, The Netherlands)
X. Wang (University of South Dakota, SD, USA)
H. Watkins (University of Oxford, UK)
M. Willis (Carolina Cardiovascular Biology Center, Chapel Hill, NC, USA)

Finanzierung / Present funding

  1. DFG Forschergruppe 604, 2005-2011: Signalling pathways in the healthy and diseased heart (Coordinator T. Eschenhagen, Principal investigator L. Carrier)
  2. EU-FP7-Health-BIG-Heart, 2010-2012: Bench-to-bedside InteGrated approach to familial hypertrophic cardiomyopathy: to the HEART of the disease (coordinator C. Redwood, Oxford; principal investigator L. Carrier)
  3. Fritz Thyssen Stiftung (Az. 10.09.1.139), 2010-2011: Familial hypertrophic cardiomyopathy: Evaluation of new molecular mechanisms and tools for therapy (principal investigator L. Carrier)

Ausgewählte Publikationen / Selected original publications (out of 70)

 

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Letzte Änderung: Frank Neumann, 19.05.2011

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