The purpose of this research
Methylated DNA-binding protein MeCP2, protein kinase CDKL5, and transcription factor FOXG1 are known as causative genes for Rett syndrome, but the relationship between these gene mutations and Rett syndrome pathology has not been clarified.
Recently, we identified a new CDKL5 mutation (Y177C). Therefore, the aim of this study is to elucidate the pathogenic mechanism of the CDKL5 mutation in Rett syndrome. Finally, we wish to produce a drug for treating Rett syndrome.
What is Rett syndrome
Rett syndrome is a rare disease that is associated with mental retardation, autism, stereotyped movements of the hands. MeCP2, CDKL5, and FOXG1 have been identified as causative genes for this disease.
Details of Rett syndrome symptoms
Symptoms of Rett syndrome caused by a mutations of MeCP2 gene include self-inflicted tendency and intellectual disability as seen from infancy. In addition, this disorder is characterized by its repetitive hand movements. Moreover, epileptic seizures, convulsions, and breathing abnormalities are often seen.
Diseases caused by mutations in the CDKL5 and FOXG1 genes are called atypical Rett syndrome. Patients with CDKL5 mutations are known to experience earlier epileptic seizures compared with MeCP2 mutations, and patients with FOXG1 mutation may develop microcephaly.
As mentioned above, it has been revealed that loss of function mutation in MeCP2, CDKL5, and FOXG1 genes is an etiology of Rett syndrome.
Effective treatments and preventive methods have not been established to date and patients only receive symptomatic treatment.
MeCP2 is identified as a causative gene for Rett syndrome and its protein regulated epigenetic systems through binding into methylated DNA. Most patients with Rett syndrome have MeCP2 mutations, but some patients have CDKL5 or FOXG1 mutations, thereby causing atypical Rett syndrome.
We previously reported a novel CDKL5 mutation (Y177C) from a Japanese atypical Rett syndrome patient. Since this mutation site was observed within the catalytic domain, we considered that this mutation led to a loss of catalytic activity.
When we examined the enzymatic activity in vitro, we could not detect the expected CDKL5 (Y177C) activity. This finding was the first report to link gene mutation with loss of enzymatic activity in our research field.
However, since the relationship between the disappearance of activity of CDKL5 and the pathology of Rett syndrome has not been elucidated at all, we have attempted to clarify the mechanism of the CDKL5 mutation on the pathology at the molecular and cellular levels.
We analyzed the CDKL5 gene sequence for a patient with Rett syndrome and determined a new mutation site of CDKL5 (red arrow in the upper figure). This mutation was substitute tyrosine (Y)-177 to cysteine (C).
When we examined the enzymatic activity in vitro, we could not detect the expected CDKL5 (Y177C) activity.
Tetsuya InazuProfessor, College of Pharmaceutical Sciences, Department of Pharmacy
Masahiro ItoProfessor, College of Life Sciences, Department of Bioinformatics
Takako KawanoAssociate Professor, College of Pharmaceutical Sciences, Department of Pharmacy
Syouichi KatayamaAsssistant Professor, College of Pharmaceutical Sciences, Department of Pharmacy
Yukihiko KubotaAssistant Professor, College of Life Sciences, Department of Bioinformatics
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