Anti-GABRB3 monoclonal antibody, clone T98-36

Background: Isodicentric 15 syndrome (IDIC-15) is due to partial duplications of chromosome 15 that may includes the q11-13 region that includes genes encoding the alpha 5 (GABRA5) and beta 3-gamma 3 (GABRB3) receptor subunits. The disease causes intellectual and physical developmental delay, seizures, intellectual disability and behavioral disorders that may be related to abnormal GABA receptor function and morphology. Seizures are often severe and may be refractory to treatment. There are however no specific guidelines for the treatment of the seizures and it is unknown whether drugs that affect the GABAergic system have a different effect in IDIC-15 seizures. Case presentation: We report the case of an adult individual with IDIC-15 whose complex-partial seizures worsened dramatically after the introduction of pregabalin, with increased seizure frequency, frequent generalization, and appearance of new seizure pattern. Her cognitive function and verbal skills also worsened during treatment with pregabalin. Her seizures and cognitive skills quickly improved after pregabalin was discontinued and treatment with lacosamide started. Discussion: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin. Conclusion: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin. sThis case may help define proper therapeutic strategies for the treatment of IDIC-15 associated seizures.

Copy number variations (CNVs) within human 15q11.2-13.3 show reduced penetrance and variable expressivity in a range of neurologic disorders. Therefore, characterizing 15q11.2-13.3 chromatin structure is important for understanding the regulation of this locus during normal neuronal development. Deletion of the Prader-Willi imprinting center (PWS-IC) within 15q11.2-13.3 disrupts long-range imprinted gene expression resulting in Prader-Willi syndrome. Previous results establish that MeCP2 binds to the PWS-IC and is required for optimal expression of distal GABRB3 and UBE3A. To examine the hypothesis that MeCP2 facilitates 15q11.2-13.3 transcription by linking the PWS-IC with distant elements, chromosome capture conformation on chip (4C) analysis was performed in human SH-SY5Y neuroblastoma cells. SH-SY5Y neurons had 2.84-fold fewer 15q11.2-13.3 PWS-IC chromatin interactions than undifferentiated SH-SY5Y neuroblasts, revealing developmental chromatin de-condensation of the locus. Out of 68 PWS-IC interactions with 15q11.2-13.3 identified by 4C analysis and 62 15q11.2-13.3 MeCP2-binding sites identified by previous ChIP-chip studies, only five sites showed overlap. Remarkably, two of these overlapping PWS-IC- and MeCP2-bound sites mapped to sites flanking CHRNA7 (cholinergic receptor nicotinic alpha 7) encoding the cholinergic receptor, nicotinic, alpha 7. PWS-IC interaction with CHRNA7 in neurons was independently confirmed by fluorescent in situ hybridization analysis. Subsequent quantitative transcriptional analyses of frontal cortex from Rett syndrome and autism patients revealed significantly reduced CHRNA7 expression compared with controls. Together, these results suggest that transcription of CHRNA7 is modulated by chromatin interactions with the PWS-IC. Thus, loss of long-range chromatin interactions within 15q11.2-13.3 may contribute to multiple human neurodevelopmental disorders.