Mutations in MAPT Gene Cause Chromosome Instability and Introduce Copy Number Variations Widely in the Genome

Article type: Research Article

Authors: Rossi, Giacomina^{a; *} | Conconi, Donatella^b | Panzeri, Elena^b | Redaelli, Serena^{b; c} | Piccoli, Elena^a | Paoletta, Laura^a | Dalprà, Leda^{b; c} | Tagliavini, Fabrizio^a

Affiliations: [a] Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy | [b] Department of Neurosciences and Biomedical Technologies, Milano-Bicocca University, Monza, Italy | [c] Medical Genetics Laboratory, S. Gerardo Hospital, Monza, Italy

Correspondence: [*] Correspondence to: Giacomina Rossi, PhD, Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy. Tel.: +39 02 2394 4582; Fax: +39 02 2394 2101; E-mail: grossi@istituto-besta.it.

Abstract: In addition to the main function of promoting polymerization and stabilization of microtubules, other roles are being attributed to tau, now considered a multifunctional protein. In particular, previous studies suggest that tau is involved in chromosome stability and genome protection. We performed cytogenetic analysis, including molecular karyotyping, on lymphocytes and fibroblasts from patients affected by frontotemporal lobar degeneration carrying different mutations in the microtubule-associated protein tau gene, to investigate the effects of these mutations on genome stability. Furthermore, we analyzed the response of mutated lymphoblastoid cell lines to genotoxic agents to evaluate the participation of tau to DNA repair systems. We found a significantly higher level of chromosome aberrations in mutated than in control cells. Mutated lymphocytes showed higher percentages of stable lesions, clonal and total aneuploidy (medians: 2 versus 0, p ≪ 0.01; 1.5 versus 0, p ≪ 0.01; 16.5 versus 0, p ≪ 0.01, respectively). Fibroblasts of patients showed higher percentages of stable lesions, structural aberrations and total aneuploidy (medians: 0 versus 0, p = 0.03; 5.8 versus 0, p = 0.02; 26.5 versus 12.6, p ≪ 0.01, respectively). In addition, the in depth analysis of DNA copy number variations showed a higher tendency to non-allelic homologous recombination in mutated cells. Finally, while our analysis did not support an involvement of tau in DNA repair systems, it revealed its role in stabilization of chromatin. In summary, our findings indicate a role of tau in genome and chromosome stability that can be ascribed to its function as a microtubule-associated protein as well as a protein protecting chromatin integrity through interaction with DNA.

Keywords: Chromosome aberrations, DNA copy number variations, genome instability, MAPT, mutation, tau protein, tauopathies

DOI: 10.3233/JAD-2012-121633

Journal: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 969-982, 2013