Inactivation of the CDKL3 gene at 5q31.1 by a balanced t(X;5) translocation associated with nonspecific mild mental retardation.
We have investigated the breakpoints of a balanced reciprocal translocation between chromosomes X and 5, [46,X,t(X;5)(p11.1;q31.1)], in a woman with mild mental retardation (MR). Methylation studies showed a 100% skewed X-inactivation in patient-derived lymphocytes. Cloning and sequencing of the junction fragment from the X derivative showed that the breakpoint occurred in intron 3 of the CDKL3 gene on chromosome 5 and in a region devoid of genes on chromosome X. Quantitative RT-PCR analyses on patient-derived lymphoblastoid cells documented a significant 50% decrease of the CDKL3 transcript level. Allelic expression analysis, using an intronic SNP that was RT-PCR amplified from CDKL3 pre-mRNA, provided further evidence that the CDKL3 gene was transcribed from only one allele. Decreased CDKL3 gene expression was definitively confirmed at the protein level by immunoblot analysis. CDKL3 is a member of a subset of the cdc2-related protein kinase family that shows similarity to both mitogen-activated protein kinases (MAPK) and cyclin-dependant kinases (cdks). Importantly, one member of the family, CDKL5, has been implicated in atypical Rett syndrome, West syndrome, and X-linked infantile spasm, all including MR as a manifestation. Expression studies demonstrated that the mouse homologue, mCdkl3, was expressed in all brain regions investigated and throughout mouse development, a pattern that is consistent with a role in development and brain function. Together the data suggest that haploinsufficiency of CDKL3 in the t(X;5) patient contributes to her phenotype, and that the CDKL3 gene is a strong candidate for nonsyndromal autosomal dominant MR.
Dubos
Aline
A
Department of Molecular Pathology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), Illkirch, France.
Pannetier
Solange
S
Hanauer
André
A
D000818:Animals; D001402:B-Lymphocytes; D002461:Cell Line, Transformed; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014178:Translocation, Genetic; D049951:X Chromosome Inactivation
C477873:CDKL3 protein, human; D017346:Protein Serine-Threonine Kinases