| 研究実績の概要 |
CDKL5 deficiency disorder (CDD) is a devastating X-linked neurodevelopmental disorder caused by pathogenic mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene. A core feature of CDD is the severe, early-onset refractory seizures, with 90% of patients displaying seizures by three months of age, which greatly impact the quality of life of patients and their families. However, little is known about the molecular and neural basis underlying seizures in CDD patients. We found that spontaneous seizures were present in Cdkl5 knockout mice (KO) on a C57BL/6J but absent on a C57BL/6N background, suggesting that genetic modifier(s) may influence seizure susceptibility in CDD. In this study, we will identify for the first time the modifier gene(s) regulating seizure susceptibility in CDD by genetic mapping and exome sequencing in a Cdkl5 knockout mouse model. The results will provide novel insights into the molecular and neural basis of epilepsy in CDD, and will open a new avenue for developing novel and effective therapeutics for refractory seizures in CDD patients.
In this year we examined whether seizure occurs in F1 Cdkl5 KO mice (B6N;B6J mixed background). Based on the results from F1 mice, we have generated N2 Cdkl5 KO mice suitable for further modifier gene mapping.
|
| 今後の研究の推進方策 |
We will examine the seizure in N2 Cdkl5 KO mice using video-EEG/EMG recording. After phenotyping N2 mice, we will extract the genomic DNA from more than 50 N2 mice with and without seizures, respectively, and perform modifier gene mapping using genetic linkage analysis and subsequently identify the gene. After identifying the modifier gene, we will analyse the physiological functions of modifier gene by molecular, biochemical and neuroscience studies.
|
