Cell cloning-based transcriptome analysis in cyclin-dependent kinase-like 5 mutation patients with severe epileptic encephalopathy.
Mutations in the human CDKL5 gene have been shown to cause infantile spasms, as well as Rett syndrome-like phenotype. Because CDKL5 is subjected to X chromosome inactivation (XCI), individual cells from CDKL5 mutation girls either express the wild-type or mutant allele, likely resulting in different consequences at both the cellular and molecular levels. To identify these consequences, we carried out gene expression profiling on clonal populations derived from primary cultures of three patients' fibroblasts either expressing the wild-type or mutant allele. A total of 16 up-regulated and 20 down-regulated genes were identified. The differentially expressed gene products, mostly involved in differentiation and oxidative stress may be related to a mechanism underlying mental retardation and epilepsy. Among these, the apoptosis signal-regulated kinase MAP3K5 expression was found to be altered in non-neuronal, but also in neuronal CDKL5-deficient cells. Due to the fact that MAP3K5 activates MAP kinase pathway, which mediates signals leading to both differentiation and survival in neuronal cells, we suggest that a CDKL5 deficit may induce changes in synaptic plasticity in the patient's brain.
CNRS UMR 8104, Institut Cochin, Université Paris Descartes, Paris, France.
Juliette
J
Nectoux
Yann
Y
Fichou
Nicolas
N
Cagnard
Nadia
N
Bahi-Buisson
Patrick
P
Nusbaum
Franck
F
Letourneur
Jamel
J
Chelly
Thierry
T
Bienvenu
D001921:Brain / Q000378:metabolism; D002999:Clone Cells; D016000:Cluster Analysis; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D065768:Lennox Gastaut Syndrome; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D013036:Spasms, Infantile / Q000235:genetics*; D049951:X Chromosome Inactivation
D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human