A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain
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The X-linked cyclin-dependent kinase-like 5 (CDKL5) gene is an important molecular determinant of early-onset intractable seizures with infantile spasms and Rett syndrome-like phenotype. The gene encodes a kinase that may influence components of molecular pathways associated with MeCP2. In humans there are two previously reported splice variants that differ in the 5′ untranslated exons and produce the same 115 kDa protein. Furthermore, very recently, a novel transcript including a novel exon (16b) has been described. By aligning both the human and mouse CDKL5 proteins to the orthologs of other species, we identified a theoretical 107 kDa isoform with an alternative C-terminus that terminates in intron 18. In human brain and all other tissues investigated except the testis, this novel isoform is the major CDKL5 transcript. The detailed characterisation of this novel isoform of CDKL5 reveals functional and subcellular localisation attributes that overlap greatly, but not completely, with that of the previously studied human CDKL5 protein. Considering its predominant expression in the human and mouse brain, we believe that this novel isoform is likely to be of primary pathogenic importance in human diseases associated with CDKL5 deficiency, and suggest that screening of the related intronic sequence should be included in the molecular genetic analyses of patients with a suggestive clinical phenotype.
KeywordsSplice Variant Pathogenic Mutation Zebra Finch Epileptic Encephalopathy Full Open Reading Frame
We would like to express our gratitude to the Rett Syndrome Australian Research Fund, the Italian association proRETT ricerca, the Rotary Club of Narellan, the Harrington Park Foundation, and the Country Women’s Association of NSW for additional financial support. This research was funded by National Health and Medical Research Council of Australia project grants 346603 (PT, JC) and 570752 (PT, JC), the E-Rare EuroRETT Network (NL), Fondazione Cariplo 2010-0724 (NL), the Italian Ministry of Research (CKN), and FP7-PEOPLE-ITN-2008 (CKN).
Conflict of interest
The authors have no conflict of interest to declare.
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