INCREASED CPA6 PROMOTER METHYLATION IN FOCAL
EPILEPSY AND INFEBRILE SEIZURES
Annick Salzmann, PhDService de Médecine Génétique (HUG)Département de Psychiatrie (UNIGE)
7ème Journée de la Recherche Clinique8 mai 2014
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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
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
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
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
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 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)
CPA6 MUTATIONS IN EPILEPTIC PATIENTS
CPA6 Protein
7 missense variants
Consanguineous FEB11/ELT5 familyc.809C>T → TT
3 FE patientsc.799G>A → GA1 TLE patient
c.843A>G → AG
1 TLE patientc.875C>G → CG
AssociationStudy
AssociationStudy
AssociationStudy
Sapio et al. J Biological Chemistry, 2012
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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
LIFE EPIGENETIC PROFIL
Foley et al. Am. J. Epidemiol. 2009
DNA METHYLATION
CCH3 GC
GCH3
METHYLATION HYPOTHESIS IN EPILEPTOGENESIS
Kobow & Blümcke, Epilepsia, 2012
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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
Young Controls
* ; # ; § ; $
** ; ## ; § § ; $ $
% M
ethy
latio
n
• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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)
Thank you for your attention
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