Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency

Chuan Tan; Chloe Shard; Enzo Ranieri; Kim Hynes; Duyen H Pham; Damian Leach; Grant Buchanan; Mark Corbett; Cheryl Shoubridge; Raman Kumar; Evelyn Douglas; Lam S Nguyen; Jacinta Mcmahon; Lynette Sadleir; Nicola Specchio; Carla Marini; Renzo Guerrini; Rikke S Moller; Christel Depienne; Eric Haan; Paul Q Thomas; Samuel F Berkovic; Ingrid E Scheffer; Jozef Gecz

doi:10.1093/hmg/ddv245

Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency

Hum Mol Genet. 2015 Sep 15;24(18):5250-9. doi: 10.1093/hmg/ddv245. Epub 2015 Jun 29.

Authors

Chuan Tan¹, Chloe Shard², Enzo Ranieri³, Kim Hynes¹, Duyen H Pham⁴, Damian Leach⁵, Grant Buchanan⁵, Mark Corbett¹, Cheryl Shoubridge⁴, Raman Kumar⁴, Evelyn Douglas³, Lam S Nguyen⁶, Jacinta Mcmahon⁷, Lynette Sadleir⁸, Nicola Specchio⁹, Carla Marini¹⁰, Renzo Guerrini¹⁰, Rikke S Moller¹¹, Christel Depienne¹², Eric Haan¹³, Paul Q Thomas², Samuel F Berkovic¹⁴, Ingrid E Scheffer¹⁴, Jozef Gecz¹⁵

Affiliations

¹ School of Paediatrics and Reproductive Health.
² School of Molecular and Biomedical Sciences.
³ SA Pathology, Adelaide, Australia.
⁴ School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
⁵ Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA, Australia.
⁶ School of Paediatrics and Reproductive Health, INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris 75015, France.
⁷ Epilepsy Research Centre, The University of Melbourne, Melbourne, VIC, Australia.
⁸ Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
⁹ Division of Neurology, Department of Neuroscience, Bambino Gesù Children's Hospital IRCCS, P.za S. Onofrio Rome 400165, Italy.
¹⁰ Neuroscience Department, Children's Hospital A. Meyer, University of Florence, Firenze, Italy.
¹¹ Danish Epilepsy Centre, Dianalund, Denmark, Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
¹² Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Sorbonne Universités, UPMC Univ Paris 06, Paris F-75013, France, Département de Génétique et de Cytogénétique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris F-75013, France.
¹³ School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia, South Australian Clinical Genetics Service, SA Pathology, North Adelaide, Australia.
¹⁴ Epilepsy Research Centre, The University of Melbourne, Melbourne, VIC, Australia, Epilepsy Research Centre, The University of Melbourne, Melbourne, Australia and Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
¹⁵ School of Paediatrics and Reproductive Health, School of Molecular and Biomedical Sciences, SA Pathology, Adelaide, Australia, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia, jozef.gecz@adelaide.edu.au.

PMID: 26123493
DOI: 10.1093/hmg/ddv245

Abstract

Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE; also known as epilepsy and mental retardation limited to females, EFMR; MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression; enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxysteroid Dehydrogenases / genetics
3-Hydroxysteroid Dehydrogenases / metabolism
Adolescent
Adult
Age of Onset
Aldo-Keto Reductase Family 1 Member C3
Cadherins / genetics*
Child
Child, Preschool
Cluster Analysis
Epilepsy / blood*
Epilepsy / diagnosis
Epilepsy / genetics*
Female
Fibroblasts / metabolism
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Humans
Hydroxyprostaglandin Dehydrogenases / genetics
Hydroxyprostaglandin Dehydrogenases / metabolism
Infant
Infant, Newborn
Intellectual Disability / genetics
Middle Aged
Mutation*
Phenotype
Pregnanolone / blood
Pregnanolone / deficiency*
Protocadherins
Reproducibility of Results
Signal Transduction
Young Adult

Substances

Cadherins
PCDH19 protein, human
Protocadherins
Pregnanolone
3-Hydroxysteroid Dehydrogenases
Hydroxyprostaglandin Dehydrogenases
AKR1C3 protein, human
Aldo-Keto Reductase Family 1 Member C3