| Literature DB >> 26123493 |
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.
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.Entities:
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Year: 2015 PMID： 26123493 DOI： 10.1093/hmg/ddv245
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150