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 HaanPaul Q Thomas, Samuel F Berkovic, Ingrid E Scheffer, Jozef Gecz

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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.

TidsskriftHuman Molecular Genetics
Udgave nummer18
Sider (fra-til)5250-5259
StatusUdgivet - 2015


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