Extensive mutational analysis of CDK5 and CDK5R1 in patients with non-syndromic mental retardation reveals novel variants in CDK5R1 3’-UTR

CDK5 and its activator p35, encoded by CDK5R1 gene, are highly expressed
in CNS where they have a fundamental role in neuronal migration and differentiation
during CNS development. Their fundamental role in CNS development
and function, and their involvement in the pathogenesis of neurodegenerative
disorders makes CDK5 and CDK5R1 strong candidate genes for
the onset of mental retardation. We carried out the mutation screening of
CDK5 and CDK5R1 coding regions, as well as of CDK5R1 3’-UTR, on a cohort
of 344 patients with non-syndromic mental retardation (NS-MR). In fact, we
recently demonstrated that 3’-UTR has a key role in the post-transcriptional
regulation of CDK5R1 expression, through the binding of protein factors and
microRNAs belonging to miR-15/107 family, and this evidence prompted us
to include this region in the mutational analysis. We found one silent mutation
in CDK5, and three silent and two missense conservative mutations in
CDK5R1 coding region. Four novel variations in intronic regions of CDK5
were also found but never predicted to cause splicing defects. Interestingly,
we found nine heterozygous variations in CDK5R1 3’-UTR: among these, six
were single base substitutions and three were small deletions. None of these
variations was present in 450 healthy controls. Of particular interest is the
deletion of one predicted miR-15/107 family binding site, found in one patient.
Luciferase constructs containing the mutations observed in CDK5R1
3’-UTR will be used to verify if these variations have an effect on CDK5R1 expression
levels and therefore constitute susceptibility variants for NS-MR