title: Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency.
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.
authors.affiliation: School of Paediatrics and Reproductive Health.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tan
authors.affiliation: School of Molecular and Biomedical Sciences.
authors.forename: Chloe
authors.initials: C
authors.lastname: Shard
authors.affiliation: SA Pathology, Adelaide, Australia.
authors.forename: Enzo
authors.initials: E
authors.lastname: Ranieri
authors.affiliation: School of Paediatrics and Reproductive Health.
authors.forename: Kim
authors.initials: K
authors.lastname: Hynes
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Duyen H
authors.initials: DH
authors.lastname: Pham
authors.affiliation: Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA, Australia.
authors.forename: Damian
authors.initials: D
authors.lastname: Leach
authors.affiliation: Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
authors.affiliation: School of Paediatrics and Reproductive Health.
authors.forename: Mark
authors.initials: M
authors.lastname: Corbett
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.affiliation: SA Pathology, Adelaide, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Douglas
authors.affiliation: 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.
authors.forename: Lam S
authors.initials: LS
authors.lastname: Nguyen
authors.affiliation: Epilepsy Research Centre, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Mcmahon
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
authors.forename: Lynette
authors.initials: L
authors.lastname: Sadleir
authors.affiliation: Division of Neurology, Department of Neuroscience, Bambino Gesù Children's Hospital IRCCS, P.za S. Onofrio Rome 400165, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.affiliation: Neuroscience Department, Children's Hospital A. Meyer, University of Florence, Firenze, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.affiliation: Neuroscience Department, Children's Hospital A. Meyer, University of Florence, Firenze, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Danish Epilepsy Centre, Dianalund, Denmark, Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Moller
authors.affiliation: 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.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: School of Molecular and Biomedical Sciences.
authors.forename: Paul Q
authors.initials: PQ
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: 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.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: 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.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000074425:Aldo-Keto Reductase Family 1 Member C3; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D004827:Epilepsy / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011280:Pregnanolone / Q000097:blood / Q000172:deficiency*; D000091363:Protocadherins; D015203:Reproducibility of Results; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins; D011280:Pregnanolone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3