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

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.

[1]  M. Rogawski,et al.  Pediatric super‐refractory status epilepticus treated with allopregnanolone , 2014, Annals of neurology.

[2]  Sven Bergmann,et al.  A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. , 2014, American journal of human genetics.

[3]  Kyoko Takano,et al.  PCDH19-related female-limited epilepsy: Further details regarding early clinical features and therapeutic efficacy , 2013, Epilepsy Research.

[4]  M. Rogawski,et al.  Neuroactive steroids for the treatment of status epilepticus , 2013, Epilepsia.

[5]  A. Cole,et al.  SGE‐102: A novel therapy for refractory status epilepticus , 2013, Epilepsia.

[6]  N. Akaike,et al.  Modulation of allopregnanolone on excitatory transmitters release from single glutamatergic terminal , 2013, Brain Research Bulletin.

[7]  A. Kelemen,et al.  Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders , 2013, neurogenetics.

[8]  J. Parsch,et al.  The evolutionary causes and consequences of sex-biased gene expression , 2013, Nature Reviews Genetics.

[9]  J. Gécz,et al.  Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability , 2012, Molecular Psychiatry.

[10]  E. Bertini,et al.  Somatic mosaicism of PCDH19 mutation in a family with low-penetrance EFMR , 2012, neurogenetics.

[11]  P. Dimova,et al.  A novel PCDH19 mutation inherited from an unaffected mother. , 2012, Pediatric neurology.

[12]  P. Deyn,et al.  Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model , 2012, Behavioural Brain Research.

[13]  H. Shiraishi,et al.  PCDH19 mutation in Japanese females with epilepsy , 2012, Epilepsy Research.

[14]  F. Vigevano,et al.  Acute‐onset epilepsy triggered by fever mimicking FIRES (febrile infection–related epilepsy syndrome): The role of protocadherin 19 (PCDH19) gene mutation , 2011, Epilepsia.

[15]  W. Miller,et al.  Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. , 2011, American journal of human genetics.

[16]  Doodipala Samba Reddy,et al.  Role of Anticonvulsant and Antiepileptogenic Neurosteroids in the Pathophysiology and Treatment of Epilepsy , 2011, Front. Endocrin..

[17]  E. Bertini,et al.  Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations , 2011, Epilepsia.

[18]  C. Harden,et al.  Hormonal Therapy for Epilepsy , 2011, Current neurology and neuroscience reports.

[19]  C. Depienne,et al.  Protocadherin 19 mutations in girls with infantile-onset epilepsy , 2011, Neurology.

[20]  M. Avoli,et al.  Chapter 7 7 Neurosteroids-Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy , 2017 .

[21]  James D. Jontes,et al.  Protocadherin-19 and N-cadherin interact to control cell movements during anterior neurulation , 2010, The Journal of cell biology.

[22]  H. Vaudry,et al.  Neurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides , 2009, Frontiers in Neuroendocrinology.

[23]  M. Rogawski,et al.  Neurosteroid replacement therapy for catamenial epilepsy , 2009, Neurotherapeutics.

[24]  M. Ruberg,et al.  Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females , 2009, PLoS genetics.

[25]  Yoav Gilad,et al.  Sex-specific genetic architecture of human disease , 2008, Nature Reviews Genetics.

[26]  Andrew Menzies,et al.  X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment , 2008, Nature Genetics.

[27]  K. Friend,et al.  Epilepsy and mental retardation limited to females: an under-recognized disorder. , 2008, Brain : a journal of neurology.

[28]  E. Giller,et al.  Clinical Evaluation of Ganaxolone in Pediatric and Adolescent Patients with Refractory Epilepsy , 2007, Epilepsia.

[29]  Hui Shen,et al.  Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits , 2007 .

[30]  J. Gécz,et al.  Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation , 2007, Nature Genetics.

[31]  Trevor M Penning,et al.  Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms. , 2007, Archives of biochemistry and biophysics.

[32]  M. McCarthy,et al.  Focal adhesion kinase and paxillin: novel regulators of brain sexual differentiation? , 2007, Endocrinology.

[33]  C. Frye,et al.  Seizure exacerbation associated with inhibition of progesterone metabolism , 2003, Annals of neurology.

[34]  N. Watson,et al.  N-Cadherin expression in motoneurons is directly regulated by androgens: a genetic mosaic analysis in rats , 2001, Brain Research.

[35]  B. Bourgeois,et al.  Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial , 2000, Epilepsy Research.

[36]  K. Laxer,et al.  Assessment of Ganaxolone's Anticonvulsant Activity Using a Randomized, Double‐Blind, Presurgical Trial Design , 2000, Epilepsia.

[37]  L. Pannell,et al.  Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. , 1998, The Journal of pharmacology and experimental therapeutics.

[38]  P. Klein,et al.  Three Patterns of Catamenial Epilepsy , 1997, Epilepsia.

[39]  Nancy B. Spinner,et al.  Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing , 1997, Nature Genetics.

[40]  R. Sparkes,et al.  Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization. , 1995, Genomics.

[41]  S. Paul,et al.  Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. , 1986, Science.

[42]  R. C. Juberg,et al.  A new familial form of convulsive disorder and mental retardation limited to females. , 1971, The Journal of pediatrics.

[43]  M. Avoli,et al.  Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy -- Jasper's Basic Mechanisms of the Epilepsies , 2012 .

[44]  Doodipala Samba Reddy,et al.  Neurosteroids: endogenous role in the human brain and therapeutic potentials. , 2010, Progress in brain research.