Format

Send to

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

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

Author information

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.

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.

PMID:
26123493
DOI:
10.1093/hmg/ddv245
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center