Copy number variations involving the microtubule-associated protein tau in human diseases

Abstract

Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs (microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated protein lacking the first MT-binding domain, which had a dramatic decrease in the binding to MTs but acquired the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from both a loss of normal function and a gain of function by which truncated tau would sequester another MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism.

DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

“…Even if there is a high prevalence of dementia, not every DS patient develops the accompanying clinical symptoms ( Nieuwenhuis-Mark, 2009 ). Interestingly, overexpression of DYRK1A and some direct targets, such as APP and MAPT, contributes to the early onset of neurofibrillary degeneration, β-amyloidosis, neuronal loss and dementia in DS ( Rovelet-Lecrux et al, 2006 , 2010 ; Salehi et al, 2006 ; Liu et al, 2008 ; Wegiel et al, 2011 ; Rovelet-Lecrux and Campion, 2012 ; Park and Chung, 2013 ).…”

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

“…Pathogenic mutations in MAPT, including CNVs, have been previously implicated in frontotemporal dementia and 17q21.31 microduplication with variable phenotype. 74 Rovelet-Lecrux et al 75 previously described a 439-kb microduplication at the 17q21.31 locus encompassing the MAPT, IMP5, CRHR1 and STH genes in the proband of a family in which three patients displayed an frontotemporal lobar dementia phenotype. In our study, only MAPT was duplicated in all three affected siblings.…”

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model

“…Mutations in the gene which encodes for tau, microtubule-associated protein tau ( MAPT ), cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), directly implicating tau dysfunction in neurodegenerative processes (Clark et al, 1998; Hutton et al, 1998; Pittman et al, 2006). Furthermore, a copy number variation (CNV) consisting of a complete duplication of the MAPT locus has been described in a patient with frontotemporal dementia (Rovelet-Lecrux and Campion, 2012). These observations suggest that abnormal forms of tau or even elevated levels of wild-type tau are sufficient to cause neuropathology.…”