title: Functional characterization of CDK5 and CDK5R1 mutations identified in patients with non-syndromic intellectual disability.
abstract: Cyclin-dependent kinase 5 (CDK5) and cyclin-dependent kinase 5, regulatory subunit 1 (CDK5R1), encoding CDK5 activator p35, have a fundamental role in central nervous system (CNS) development and function, and are involved in the pathogenesis of several neurodegenerative disorders, thus constituting strong candidate genes for the onset of intellectual disability (ID). We carried out a mutation screening of CDK5 and CDK5R1 coding regions and CDK5R1 3'-UTR on a cohort of 360 patients with non-syndromic ID (NS-ID) using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. We found one novel silent mutation in CDK5 and one novel silent mutation in CDK5R1 coding regions, three novel intronic variations in CDK5, not causing any splicing defect, and four novel heterozygous variations in CDK5R1 3'-UTR. None of these variations was present in 450 healthy controls and single-nucleotide polymorphism (SNP) databases. The functional study of CDK5R1 p.A108V mutation evidenced an impaired p35 cleavage by the calcium-dependent protease calpain. Moreover, luciferase constructs containing the CDK5R1 3'-UTR mutations showed altered gene expression levels. Eight known polymorphisms were also identified displaying different frequencies in NS-ID patients compared with the controls. In particular, the minor allele of CDK5R1 3'-UTR rs735555 polymorphism was associated with increased risk for NS-ID. In conclusion, our data suggest that mutations and polymorphisms in CDK5 and CDK5R1 genes may contribute to the onset of the NS-ID phenotype.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moncini
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Castronovo
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova, Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Murgia
authors.affiliation: Laboratorio di Citogenetica e Genetica Molecolare, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.affiliation: UOSD Genetica Medica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Bedeschi
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Lunghi
authors.affiliation: UOS Genetica, Clinica Pediatrica, Fondazione Monza Brianza per il Bambino e la Mamma, Ospedale San Gerardo, Università degli Studi Milano-Bicocca, Monza, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Ospedale San Luca, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bonati
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.identifier: http://orcid.org/0000-0001-6481-8467
authors.initials: P
authors.lastname: Riva
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0002-5871-9689
authors.initials: M
authors.lastname: Venturin
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D002648:Child; D002851:Chromatography, High Pressure Liquid; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D007438:Introns; D007805:Language Development Disorders / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5