Photochromism of dihydroquinolines

Reversible photochromic reactions, in which absorption spectrum of chemical compound may be shifted by application of visible or ultraviolet light, and then returned to original state by heating, are observed for certain members of 1,2-dihydroquinoline family. Structural formulas for colorless and colored states are given

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

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.Duyen H. Pham, Chuan C. Tan, Claire C. Homan, Kristy L. Kolc, Mark A. Corbett, Dale McAninch, Archa H. Fox, Paul Q. Thomas, Raman Kumar Jozef Gec

A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity

Epilepsy and Mental Retardation Limited to Females (EFMR) is an infantile onset disorder characterized by clusters of seizures. EFMR is due to mutations in the X-chromosome gene PCDH19, and is underpinned by cellular mosaicism due to X-chromosome inactivation in females or somatic mutation in males. This review characterizes the neuropsychiatric profile of this disorder and examines the association of clinical and molecular factors with neuropsychiatric outcomes. Data were extracted from 38 peer-reviewed original articles including 271 individual cases. We found that seizure onset ≤12 months was significantly associated (p = 4.127 × 10⁻⁷) with more severe intellectual disability, compared with onset >12 months. We identified two recurrent variants p.Asn340Ser and p.Tyr366Leufs*10 occurring in 25 (20 unrelated) and 30 (11 unrelated) cases, respectively. PCDH19 mutations were associated with psychiatric comorbidities in approximately 60% of females, 80% of affected mosaic males, and reported in nine hemizygous males. Hyperactive, autistic, and obsessive-compulsive features were most frequently reported. There were no genotype-phenotype associations in the individuals with recurrent variants or the group overall. Age at seizure onset can be used to provide more informative prognostic counseling.Kristy L Kolc, Lynette G Sadleir, Ingrid E Scheffer, Atma Ivancevic, Rachel Roberts, Duyen H Pham, Jozef Gec

Levetiracetam efficacy in PCDH19 Girls Clustering Epilepsy

BACKGROUND:PCDH19 Girls clustering epilepsy (GCE) has a phenotypic spectrum that includes developmental and epileptic encephalopathy. PCDH19-GCE presents with clusters of seizures in the first years of life. Although patients typically outgrow their seizures, many are left with intellectual disability. Here we retrospectively assess the effect of levetiracetam in two independent cohorts of females with PCDH19-GCE. METHODS:Cohort A was identified by searching our epilepsy genetics research database for girls with PCDH19-GCE who had trialled levetiracetam. Cohort B consisted of girls aged 2 years or older, including women, participating in an international online questionnaire. Information regarding seizure frequency and levetiracetam use was obtained by in-person patient interview and review of clinical records for cohort A, and by patient report for cohort B. RESULTS:Cohort A consisted of 17 females, aged 3-37 years, who had a trial of levetiracetam at an average age of 10.7 years. 13/17 females became seizure free for >12 months; while 10/17 remained seizure free for >24 months. Cohort B comprised 62 females, aged 1.5-41 years. 26/62 became seizure free for >12 months, and 19/62 for >24 months on levetiracetam therapy. DISCUSSION:Levetiracetam was effective in two cohorts of females with PCDH19-GCE where 42% and 76% of females became seizure free for >12 months, respectively. Levetiracetam is an effective therapy for females with PCDH19-GCE and should be considered early in the management of the highly refractory clusters of seizures that characterise this genetic disease.Lynette G. Sadleir, Kristy L. Kolc, Chontelle King, Heather C. Mefford, Russell C. Dale, Jozef Gecz, Ingrid E. Scheffe