Abstract
Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20–30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem.
Highlights
Frontotemporal lobar degeneration (FTLD) consists of a group of disorders that manifest as the result of an initial pathological damage of the frontal and temporal lobes of the cerebrum [2, 19, 21]
We report a novel missense mutation in microtubule-associated protein tau gene (MAPT) in a 67-yearold lady who was referred with dementia and non-fluent
N296N and N296H lead to an increase in 4R tau mRNA, while mutation ΔN296 has no effect on alternative mRNA splicing of MAPT [11, 28]
Summary
Frontotemporal lobar degeneration (FTLD) consists of a group of disorders that manifest as the result of an initial pathological damage of the frontal and temporal lobes of the cerebrum [2, 19, 21]. Hereditary forms represent 20–30 % of all cases of FTLD and up to 15–20 % of these carry mutations in MAPT, the gene coding for the microtubule-associated protein tau [22]. Patients carrying MAPT mutations are characterized by filamentous and hyperphosphorylated tau inclusions in neuronal and glial. Parmar Department of Experimental Medical Science and Lund Stem Cell Center, Lund University, Lund, Sweden. Revesz Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
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