Chromosome 17-linked Frontotemporal dementia with Ubiquitin-Positive, Tau-Negative Inclusions

Summary

Familial forms of frontotemporal dementia (FTD) are in 10–43% of patients, caused by mutations in the gene encoding the microtubule associated protein tau (MAPT) located at chromosome 17q21. Neuropathologically, these patients are characterized by tau-positive depositions in brain. However, autosomal dominant forms of FTD without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. One such form is FTD linked to 17q21, with tau-negative but ubiquitine-positive neuronal inclusions or FTD-U. We previously reduced the candidate chromosomal region to 4.8 cM in a Dutch FTD-U family, 1083. A mutation in MAPT was excluded by genomic sequencing. More recently, we identified three Belgian FTD families of which two, DR2 and DR8, showed linkage to the 17q21 region. Both families shared a common haplotype in an 8.04 cM region, indicating that they are genetically related to a common founder. In the third family, DR7, we obtained an autopsy confirmation of the characteristic ubiquitin-positive, tau-negative neuronal inclusions. Currently, there are 11 FTD families linked to 17q21 that do not segregate a MAPT mutation, of which five are conclusively linked (LOD score > 3). Together the data suggest that FTD-U could represent an important subtype of FTD, and that identification of the underlying gene defect might significantly contribute to our understanding of the pathomechanism leading to neurodegeneration in this dementia subtype.