CDK5 and CDK5R1, encoding CDK5 activator p35, have a fundamental role in 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 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 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 to the controls. In particular, the minor allele of CDK5R1 3'-UTR rs735555 polymorphism was associated to 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.

Functional characterization of CDK5 and CDK5R1 mutations identified in patients with non-syndromic intellectual disability / S. Moncini, P. Castronovo, A. Murgia, S. Russo, M.F. Bedeschi, M. Lunghi, A. Selicorni, M.T. Bonati, P. Riva, M. Venturin. - In: JOURNAL OF HUMAN GENETICS. - ISSN 1434-5161. - 61:4(2016 Apr), pp. 283-293.

Functional characterization of CDK5 and CDK5R1 mutations identified in patients with non-syndromic intellectual disability

S. Moncini
Primo
;
P. Castronovo
Secondo
;
M. Lunghi;P. Riva
Penultimo
;
M. Venturin
2016-04

Abstract

CDK5 and CDK5R1, encoding CDK5 activator p35, have a fundamental role in 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 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 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 to the controls. In particular, the minor allele of CDK5R1 3'-UTR rs735555 polymorphism was associated to 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.
cyclin-dependent kinase-5; mental-retardation; regulatory elements; Alzheimers-disease; messenger-RNA; genes; P35; activator; regions; neurodegeneration
Settore BIO/13 - Biologia Applicata
10-dic-2015
Article (author)
File in questo prodotto:
File Dimensione Formato  
6177_2_merged_1445962556.pdf

accesso riservato

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 1.24 MB
Formato Adobe PDF
1.24 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/380527
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 8
social impact