Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP‐17 family

Abstract

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant condition clinically characterized by behavioral, cognitive and motor disturbances. It was recently discovered that the majority of the FTDP-17 families carry missense or 5' splice mutations in the exons coding for the microtubule-binding domains of the tau protein. However, in at least five FTDP-17 families, no such mutations could be identified. In the present study, we aimed at further investigate abnormalities in the tau gene in a Swedish FTDP-17 family, where no mutations in the tau gene previously have been identified. Initially, we searched for larger deletions by Southern blot hybridization. Furthermore, possible abnormal splicing events was investigated by RT-PCR from brain tissue of affected individuals. In addition, we investigated the presence of mutations in other genes in the FTDP-17 candidate region on chromosome 17q21; Gamma-tubulin, Glial Fibrillary Acid Protein (GFAP), Human dual specificity phosphatase tyrosine/serine (VHR), Rap-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. In conclusion, no pathological changes in the tau gene were observed, neither was any mutations segregating with the disease detected in the investigated candidate genes. Further investigation of extended intron sequences or promoter regions of the tau gene and additional candidate genes on chromosome 17q21, therefore seems to be necessary in order to identify the additional causes of FTDP-17.

Pathological Heterogeneity of Frontotemporal Lobar Degeneration with Ubiquitin-Positive Inclusions Delineated by Ubiquitin Immunohistochemistry and Novel Monoclonal Antibodies

“…14 -17 Although this is the same chromosomal region in which the tau gene is located, no tau mutations have been found in any of these families, and patients from these families have not been found to have tauopathy on neuropathological examination. [15][16][17] To date, no genetic mutation responsible for FTLD-U in these chromosome 17-linked families has been found. Three genetic loci on chromosome 9 have also been linked to familial forms of FTD.…”

“…8 -12 Although most FTLD-U cases are sporadic, several families exhibiting autosomal dominant inheritance patterns of FTLD-U neuropathology have been linked to chromosomes 9 and 17. [13][14][15][16][17] No genetic mutations on chromosomes 9 and 17 responsible for the disease in these families, however, have been found to date, and the molecular pathogenesis underlying FTLD-U remains unknown. In the present study, examination of ubiquitinimmunostained sections from 36 postmortem-confirmed FTLD-U cases was performed to gain insights into the pathological basis of FTLD-U.…”

Clinical and Molecular Aspects of Frontotemporal Dementia

“…A third explanation would be that the chromosome 17 linkage data were false-positive for these pedigrees and that the true gene would be situated on another chromosome. In the Swedish tau-negative FTDP-17 family, we have made extensive investigations of the tau gene in addition to mutation screening of 6 other candidate genes on chromosome 17q21, however, with negative findings [59]. We can thus not yet fully exclude any of the suggested explanations.…”

Neurodegenerative Disorders: The Role of Genetic Factors in Their Origin and the Efficiency of Treatment

“…Genotyping of 12 families with hereditary PD did not reveal any association between these factors. With a Swedish family affected by PD and dementia, an attempt was made to associate these diseases with mutations of the FD , γ -tubulin, glial fibrillar acidic protein (GFAP), p35, Tyr/Ser phosphatase, RPIP8 (Rap-associated protein), and τ -protein genes [78]. Mutations associated with the two diseases were not identified, suggesting the necessity of further investigation.…”