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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind24
Udgave nummer18
Sider (fra-til)5250-5259
ISSN0964-6906
DOI
StatusUdgivet - 2015

Fingeraftryk

Pregnanolone
Mutation
Neurotransmitter Agents
GABA Modulators
Hormones
GABA Receptors
Transcriptome
Fibroblasts

Citer dette

Tan, C., Shard, C., Ranieri, E., Hynes, K., Pham, D. H., Leach, D., ... Gecz, J. (2015). Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. Human Molecular Genetics, 24(18), 5250-5259. https://doi.org/10.1093/hmg/ddv245
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. I: Human Molecular Genetics. 2015 ; Bind 24, Nr. 18. s. 5250-5259.
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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.",
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",
note = "{\circledC} The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2015",
doi = "10.1093/hmg/ddv245",
language = "English",
volume = "24",
pages = "5250--5259",
journal = "Human Molecular Genetics",
issn = "0964-6906",
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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, bind 24, nr. 18, s. 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.

I: Human Molecular Genetics, Bind 24, Nr. 18, 2015, s. 5250-5259.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015

Y1 - 2015

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.

U2 - 10.1093/hmg/ddv245

DO - 10.1093/hmg/ddv245

M3 - Journal article

C2 - 26123493

VL - 24

SP - 5250

EP - 5259

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 18

ER -