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

Tan, Chuan; Shard, Chloe; Ranieri, Enzo; Hynes, Kim; Pham, Duyen; Leach, Damien A.; Buchanan, Grant; Corbett, Mark; Shoubridge, Cheryl; Kumar, Raman; Douglas, Evelyn; Nguyen, Lam Son; McMahon, Jacinta M.; Sadleir, Lynette G.; Specchio, Nicola; Marini, Carla; Guerrini, Renzo; Møller, Rikke S.; Depienne, Christel; Haan, Eric; Thomas, Paul Q.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Gécz, Jozef

doi:10.1093/hmg/ddv245

Cited by 94 publications

(90 citation statements)

References 36 publications

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“…In our previous study, we gained indirect evidence of a likely role of nuclear hormone receptors in the pathology of PCDH19-FE (12). To examine this further we took advantage of various breast cancer cell lines including MCF-7.…”

Section: Resultsmentioning

confidence: 99%

“…We have recently shown that neurosteroids may play a significant role in the pathology of PCDH19-FE (12). We found that allopregnanolone levels were low in the blood of PCDH19-FE girls and that genes regulated by estrogen, progesterone and androgen receptors were among the most significantly dysregulated in patient primary skin cells (12). …”

Section: Introductionmentioning

confidence: 99%

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Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

Pham

Tan

Homan

et al. 2017

Human Molecular Genetics

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De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERα-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERα axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

Pham

Tan

Homan

et al. 2017

Human Molecular Genetics

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“…One hypothesis is that sexually dimorphic genes compensate for the loss of functional Pcdh19 in males. For example, 2 sexually dimorphic genes, AKRIC2 and AKRIC3 , are dysregulated in PCDH19 mutation-positive females [140]. These genes are regulated by steroid receptors and encode metabolizing enzymes for allopregnanolone, a neurosteroid that associates with and modulates GABA A receptors, causing prolonged hyperpolarization and preventing overexcitability.…”

Section: Roles In Behavior and Neurological Or Neurodevelopmental Dismentioning

confidence: 99%

“…These genes are regulated by steroid receptors and encode metabolizing enzymes for allopregnanolone, a neurosteroid that associates with and modulates GABA A receptors, causing prolonged hyperpolarization and preventing overexcitability. AKRIC2 and AKRIC3 mRNA, AKRIC3 protein, and allopregnanolone blood levels are all decreased in patients with PCDH19 mutations [140]. Another hypothesis proposes cellular interference as a mechanism for male sparing in PCDH19 mutation disorders.…”

Section: Roles In Behavior and Neurological Or Neurodevelopmental Dismentioning

confidence: 99%

Regulation of neural circuit formation by protocadherins

Peek

Mah

Weiner

2017

Cell. Mol. Life Sci.

112

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The Protocadherins (Pcdhs), which make up the most diverse group within the cadherin superfamily, were first discovered in the early 1990's. Data implicating the Pcdhs, including ∼60 proteins encoded by the tandem Pcdha, Pcdhb, and Pcdhg gene clusters and another ∼10 non-clustered Pcdhs, in the regulation of neural development has continually accumulated, with a significant expansion of the field over the past decade. Here, we review the many roles played by clustered and non-clustered Pcdhs in multiple steps important for the formation and function of neural circuits, including dendrite arborization, axon outgrowth and targeting, synaptogenesis, and synapse elimination. We further discuss studies implicating mutation or epigenetic dysregulation of Pcdh genes in a variety of human neurodevelopmental and neurological disorders. With recent structural modeling of Pcdh proteins, the prospects for uncovering molecular mechanisms of Pcdh extracellular and intracellular interactions, and their role in normal and disrupted neural circuit formation, are bright.

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“…For comparison, we included the clinically relevant drugs clonazepam and ganaxolone. Clonazepam has been used widely as a treatment for anxiety as well as seizure disorders, whereas ganaxolone is currently in clinical trials as an adjunct for the treatment of epilepsy [17–19, 26]. Information on the behavioral effects of clonazepam and ganaxolone are available for the drugs alone [27–29]; however, mixtures of these drugs have not been evaluated to our knowledge.…”

Section: Introductionmentioning

confidence: 99%

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Gunter

Platt

Rowlett

2015

Pharmacology Biochemistry and Behavior

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Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly have clinical value, their use is associated with unwanted side effects such as sedation and motor impairment. Neuroactive steroids are endogenous modulators of GABAA receptors and recent evidence has shown that combinations of the triazolo-benzodiazepine triazolam and the endogenous neuroactive steroid pregnanolone can produce both supra-additive anxiolytic effects and infra-additive reinforcing effects. In the present study, we investigated these same combinations as well as combinations of two clinically-relevant drugs from different chemical classes, the 1, 4 substituted (7-nitro) benzodiazepine clonazepam and the synthetic neuroactive steroid ganaxolone, in rats trained under a 10-response, fixed ratio (FR) schedule of food reinforcement. All four drugs induced a significant and dose-dependent suppression of food-maintained responding. From the dose-response functions, ED50s (i.e., the doses that engendered 50% of the maximum rate-decreasing effect) were generated for each drug. Dose-response functions for combinations of triazolam/pregnanolone, clonazepam/ganaxolone, triazolam/ganaxolone, and clonazepam/pregnanolone were then determined. Isobolographic analysis of the rate-decreasing effects of these combinations revealed that the potencies of the triazolam/pregnanolone combinations were supra-additive while the clonazepam/ganaxolone combinations were additive or infra-additive in relation to predicted values based on dose-additive effects. Furthermore, mixtures of clonazepam/pregnanolone were supra-additive while triazolam/ganaxolone combinations were additive, infra-additive and supra-additive. These results suggest that the ability of benzodiazepine and neuroactive steroid combinations to attenuate rates of food-maintained responding depends critically on both the constituent drugs and the dose of drug in the mixtures.

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

Cited by 94 publications

References 36 publications

Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

Regulation of neural circuit formation by protocadherins

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

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