INCREASED CPA6 PROMOTER
METHYLATION IN FOCAL
EPILEPSY AND IN
FEBRILE SEIZURES
Annick Salzmann, PhD
Service de Médecine Gén...
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylati...
EPILEPSY
• Chronic neurological disorder à affects all ages
• Defined by 2 or more unprovoked seizures
• 50 million people...
FOCAL EPILEPSY
• Most common form of epilepsy (60%)
• Localisation-related – Temporal lobe epilepsy
• Resistance to anti-e...
FEBRILE SEIZURES
• Not considered to be an epileptic condition
• Provoked by fever (>38.5°)
• Prevalence: 2–5%
• Onset age...
CONSANGUINEOUS FAMILY
7
Complex Febrile Seizures + Temporal Lobe Epilepsy
Complex Febrile Seizures
One Simple Febrile Seiz...
CARBOXYPEPTIDASE A6
(CPA6) MUTATION
CPA6 Protein
Salzmann et al. Hum Mutat, 2012
CARBOXYPEPTIDASE A6 (CPA6)
• Member of the M14 metallocarboxypeptidase family
• Highly expressed in human embryonic brain ...
CPA6 MUTATIONS IN
EPILEPTIC PATIENTS
CPA6 Protein
7 missense variants
Consanguineous
FEB11/ELT5 family
c.809C>T → TT
3 FE ...
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylati...
EPIGENETICS
• Regulation of biological processes from conception to death
of an organism
• Mitotically and/or meiotically ...
LIFE EPIGENETIC PROFIL
Foley et al.Am. J. Epidemiol. 2009
DNA METHYLATION
C
CH3
G
C
GCH3
METHYLATION HYPOTHESIS
IN EPILEPTOGENESIS
Kobow & Blümcke, Epilepsia, 2012
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylati...
CPA6 CpGs IN PROMOTER
EPILEPTIC PATIENTS &
CONTROLS
INCREASED LEVEL OF
CPA6 METHYLATION
0
1
2
3
4
5
6
7
8
Controls FE FS
Treated
Controls
with AEDs
Healthy
Children
with FHE
...
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylati...
PERSPECTIVES
• In epilepsy field à Beginning of epigenetics research à A
few published studies and most related to DNA me...
Thank you for your attention
7ème Journée de la Recherche Clinique: Increased CPA6 promoter methylation in focal epilepsy...
7ème Journée de la Recherche Clinique: Increased CPA6 promoter methylation in focal epilepsy...
7ème Journée de la Recherche Clinique: Increased CPA6 promoter methylation in focal epilepsy...
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7ème Journée de la Recherche Clinique: Increased CPA6 promoter methylation in focal epilepsy...

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Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures de A. Salzmann lors de la 7ème Journée de la Recherche Clinique

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7ème Journée de la Recherche Clinique: Increased CPA6 promoter methylation in focal epilepsy...

  1. 1. INCREASED CPA6 PROMOTER METHYLATION IN FOCAL EPILEPSY AND IN FEBRILE SEIZURES Annick Salzmann, PhD Service de Médecine Génétique (HUG) Département de Psychiatrie (UNIGE) 7ème Journée de la Recherche Clinique 8 mai 2014
  2. 2. • Epilepsy • Focal Epilepsy & Febrile Seizures • Carboxypeptidase A6 (CPA6) • Epigenetics of epilepsy • CPA6 DNA Methylation & Epilepsy • Perspectives
  3. 3. EPILEPSY • Chronic neurological disorder à affects all ages • Defined by 2 or more unprovoked seizures • 50 million people worldwide (WHO 2009) • 0.5–1% world population • Epileptic phenomenen ‣ Hyperexcitability & Hypersynchrony
  4. 4. FOCAL EPILEPSY • Most common form of epilepsy (60%) • Localisation-related – Temporal lobe epilepsy • Resistance to anti-epileptic drugs • Surgical resection of anterior temporal lobe structures • Antecedent of febrile seizures • Complex disorder = genetic + environment
  5. 5. FEBRILE SEIZURES • Not considered to be an epileptic condition • Provoked by fever (>38.5°) • Prevalence: 2–5% • Onset age: 3 months and 5 years • Epilepsy occurs 2–10 times more • Important genetic predisposition
  6. 6. CONSANGUINEOUS FAMILY 7 Complex Febrile Seizures + Temporal Lobe Epilepsy Complex Febrile Seizures One Simple Febrile Seizure Several Simple Febrile Seizures 1 2 5 3 4 5 6 4 II III 1 2 3 6 7 8 9 10 I M/– M/– M/– M/– Founder mutation = M M/M M/M M/M M/MM/– or –/– M/– or –/– M/– or –/– M/– or M/M Common Ancestor Autosomal Recessive Model
  7. 7. CARBOXYPEPTIDASE A6 (CPA6) MUTATION CPA6 Protein Salzmann et al. Hum Mutat, 2012
  8. 8. CARBOXYPEPTIDASE A6 (CPA6) • Member of the M14 metallocarboxypeptidase family • Highly expressed in human embryonic brain and in fetal umbilical cord blood (Wei et al., J. Biol. Chem. 2002) • 50-kDa pro-CPA6 → 37-kDa active form secreted into the extracellular matrix (Lyons et al., J. Biol. Chem. 2008) • Cleaves C-terminal hydrophobic residues → role in neuropeptides regulation (Lyons et al., J. Biol. Chem. 2008)
  9. 9. CPA6 MUTATIONS IN EPILEPTIC PATIENTS CPA6 Protein 7 missense variants Consanguineous FEB11/ELT5 family c.809C>T → TT 3 FE patients c.799G>A → GA1 TLE patient c.843A>G → AG 1 TLE patient c.875C>G → CG Association Study Association Study Association Study Sapio et al. J Biological Chemistry, 2012
  10. 10. • Epilepsy • Focal Epilepsy & Febrile Seizures • Carboxypeptidase A6 (CPA6) • Epigenetics of epilepsy • CPA6 DNA Methylation & Epilepsy • Perspectives
  11. 11. EPIGENETICS • Regulation of biological processes from conception to death of an organism • Mitotically and/or meiotically heritable variations in gene functions, which are not due to changes in DNA sequence • Essential for normal development, maintenance of cellular homeostasis and functions of an adult organism
  12. 12. LIFE EPIGENETIC PROFIL Foley et al.Am. J. Epidemiol. 2009
  13. 13. DNA METHYLATION C CH3 G C GCH3
  14. 14. METHYLATION HYPOTHESIS IN EPILEPTOGENESIS Kobow & Blümcke, Epilepsia, 2012
  15. 15. • Epilepsy • Focal Epilepsy & Febrile Seizures • Carboxypeptidase A6 (CPA6) • Epigenetics of epilepsy • CPA6 DNA Methylation & Epilepsy • Perspectives
  16. 16. CPA6 CpGs IN PROMOTER
  17. 17. EPILEPTIC PATIENTS & CONTROLS
  18. 18. INCREASED LEVEL OF CPA6 METHYLATION 0 1 2 3 4 5 6 7 8 Controls FE FS Treated Controls with AEDs Healthy Children with FHE Young Controls * ; # ; § ; $ ** ; ## ; § § ; $ $ %Methylation
  19. 19. • Epilepsy • Focal Epilepsy & Febrile Seizures • Carboxypeptidase A6 (CPA6) • Epigenetics of epilepsy • CPA6 DNA Methylation & Epilepsy • Perspectives
  20. 20. PERSPECTIVES • In epilepsy field à Beginning of epigenetics research à A few published studies and most related to DNA methylation • New cohorts of patients à Blood (DNA) collected after a first seizure à Blood (DNA) collected after X seizures à Comparison of DNA methylation level (EpiGenome wide)
  21. 21. Thank you for your attention

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