title: Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease.
abstract: BACKGROUND
  Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease.
  
  
  METHODS
  We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII.
  
  
  RESULTS
  No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity.
  
  
  CONCLUSIONS
  We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, BC, Canada. ian.mackenzie@vch.ca
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Stefanie L
authors.initials: SL
authors.lastname: Butland
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Devon
authors.forename: Emily
authors.initials: E
authors.lastname: Dwosh
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: Caroline
authors.initials: C
authors.lastname: Lindholm
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Neal
authors.forename: B F Francis
authors.initials: BF
authors.lastname: Ouellette
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
mesh_terms: D001921:Brain / Q000473:pathology; D003704:Dementia / Q000235:genetics* / Q000473:pathology*; D003937:Diagnosis, Differential; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics* / Q000473:pathology*; D010455:Peptides / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D010455:Peptides; C097188:polyglutamine