Characterisation of CDKL5 Transcript Isoforms in Human and Mouse.
Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3'-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders.
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Ralph D
http://orcid.org/0000-0002-3778-1483
RD
Hector
Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.
Owen
O
Dando
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Nicoletta
N
Landsberger
Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, Busto Arsizio, Italy.
Charlotte
C
Kilstrup-Nielsen
Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.
Peter C
PC
Kind
School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Mark E S
ME
Bailey
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Stuart R
SR
Cobb
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D009154:Mutation; D010641:Phenotype; D026723:Polyadenylation / Q000235:genetics; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human