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 Haan & 4 others Paul Q. Thomas, Samuel F. Berkovic, Ingrid E. Scheffer, Jozef Gecz

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

LanguageEnglish
Pages5250-5259
Number of pages10
JournalHuman molecular genetics
Volume24
Issue number18
DOIs
Publication statusPublished - 9 Apr 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Tan, Chuan ; Shard, Chloe ; Ranieri, Enzo ; Hynes, Kim ; Pham, Duyen H. ; Leach, Damian ; Buchanan, Grant ; Corbett, Mark ; Shoubridge, Cheryl ; Kumar, Raman ; Douglas, Evelyn ; Nguyen, Lam S. ; Mcmahon, Jacinta ; Sadleir, Lynette ; Specchio, Nicola ; Marini, Carla ; Guerrini, Renzo ; Moller, Rikke S. ; Depienne, Christel ; Haan, Eric ; Thomas, Paul Q. ; Berkovic, Samuel F. ; Scheffer, Ingrid E. ; Gecz, Jozef. / Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. In: Human molecular genetics. 2015 ; Vol. 24, No. 18. pp. 5250-5259.
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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.",
author = "Chuan Tan and Chloe Shard and Enzo Ranieri and Kim Hynes and Pham, {Duyen H.} and Damian Leach and Grant Buchanan and Mark Corbett and Cheryl Shoubridge and Raman Kumar and Evelyn Douglas and Nguyen, {Lam S.} and Jacinta Mcmahon and Lynette Sadleir and Nicola Specchio and Carla Marini and Renzo Guerrini and Moller, {Rikke S.} and Christel Depienne and Eric Haan and Thomas, {Paul Q.} and Berkovic, {Samuel F.} and Scheffer, {Ingrid E.} and Jozef Gecz",
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Tan, C, Shard, C, Ranieri, E, Hynes, K, Pham, DH, Leach, D, Buchanan, G, Corbett, M, Shoubridge, C, Kumar, R, Douglas, E, Nguyen, LS, Mcmahon, J, Sadleir, L, Specchio, N, Marini, C, Guerrini, R, Moller, RS, Depienne, C, Haan, E, Thomas, PQ, Berkovic, SF, Scheffer, IE & Gecz, J 2015, 'Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency', Human molecular genetics, vol. 24, no. 18, pp. 5250-5259. https://doi.org/10.1093/hmg/ddv245

Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. / Tan, Chuan; Shard, Chloe; Ranieri, Enzo; Hynes, Kim; Pham, Duyen H.; Leach, Damian; Buchanan, Grant; Corbett, Mark; Shoubridge, Cheryl; Kumar, Raman; Douglas, Evelyn; Nguyen, Lam S.; Mcmahon, Jacinta; Sadleir, Lynette; Specchio, Nicola; Marini, Carla; Guerrini, Renzo; Moller, Rikke S.; Depienne, Christel; Haan, Eric; Thomas, Paul Q.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Gecz, Jozef.

In: Human molecular genetics, Vol. 24, No. 18, 09.04.2015, p. 5250-5259.

Research output: Contribution to journalArticle

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T1 - Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency

AU - Tan, Chuan

AU - Shard, Chloe

AU - Ranieri, Enzo

AU - Hynes, Kim

AU - Pham, Duyen H.

AU - Leach, Damian

AU - Buchanan, Grant

AU - Corbett, Mark

AU - Shoubridge, Cheryl

AU - Kumar, Raman

AU - Douglas, Evelyn

AU - Nguyen, Lam S.

AU - Mcmahon, Jacinta

AU - Sadleir, Lynette

AU - Specchio, Nicola

AU - Marini, Carla

AU - Guerrini, Renzo

AU - Moller, Rikke S.

AU - Depienne, Christel

AU - Haan, Eric

AU - Thomas, Paul Q.

AU - Berkovic, Samuel F.

AU - Scheffer, Ingrid E.

AU - Gecz, Jozef

PY - 2015/4/9

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N2 - 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.

AB - 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.

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