A novel C-terminal truncated mutation in hCDKL5 protein causing a severe West syndrome: Comparison with previous truncated mutations and genotype/phenotype correlation.

West Syndrome is a severe epileptic encephalopathy characterized by epileptic spasms, hypsarrhythmia, and regression of psychomotor acquisitions beginning in the first year of life. ARX and CDKL5 genes were identified as linked to the most frequent genetic causes of West Syndrome. The present study reports the clinical, molecular and bioinformatic investigation of the patient with severe West syndrome. Molecular analysis of the two candidate genes, i.e. ARX and CDKL5 showed the presence of a novel insertion c.2788insG in exon 19 of CDKL5 gene. This mutation causes changes in cis regulation elements of exon 19 splicing and in secondary pre-mRNA structure leading probably to inclusion of alternative exon 19 in hCDKL5_5 isoform for which foetal brain expression was recently confirmed. This insertion led also to a frameshift mutation and generated a premature stop codon (p.E930Gfs9X) in the C- terminal domain and causing the lack of a part of the signal recognized by proteasome as well as the lack of peptidase I serine active site. Moreover, we review previously described, truncated mutations occurring in different regions of the C- terminal domain, and we compared the subcellular mutated protein localization and their resulting patients' phenotypes. The impairment of alternative splicing of exon 19 and the lack of a part of the proteasome signal due to c.2788insG mutation could disrupt the dynamic regulation of isoform levels especially hCDKL5_5 and hCDKL5_1 during pre and postnatal neurodevelopment and then could cause pathogenic phenotype. Signal peptidase I serine active site seems to modulate hCDKL5_5 movements between nucleus and cytoplasm. We noticed that the resulting phenotypes from truncated mutations among the C-terminal domain of hCDKL5 are almost similar and are always severe.

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