A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17

Ian R. Mackenzie, Matthew Baker, Gemma West, John Woulfe, Najeeb Qadi, Jennifer Gass, Ashley Cannon, Jennifer Adamson, Howard Feldman, Caroline Lindholm, Stacey Melquist, Rachel Pettman, A. Dessa Sadovnick, Emily Dwosh, Sidney W. Whiteheart, Michael Hutton, Stuart M. Pickering-Brown

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-I that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.

Original languageEnglish
Pages (from-to)853-867
Number of pages15
Issue number4
StatePublished - Apr 2006

Bibliographical note

Funding Information:
Funding for the work was provided by the Medical Research Council UK and Smith Foundation (to S.P.B.), the Mayo Clinic ADRC (P50 AG16574) and the Mayo Foundation (both to M.H. NIH post-doctoral fellowship grant to SM #AG 024030.). Dr Ian Mackenzie and Dr Howard Feldman gratefully acknowledge the funding of the Canadian Institutes of Health Research (CIHR) grant no. 74580. The authors wish to thank Dr Andrew Kertesz and the Division of Neuropathology at the London Health Sciences Centre and Dr Peter Heutink (Vrije University, Amsterdam, The Netherlands) for allowing us to review the pathological material on their cases. Dr Catherine Joachim (Department of Neuropathology, The Radcliffe Infirmary, Oxford) and Professor David Smith, OPTIMA project, the Radcliffe Infirmary, Oxford) are also thanked for supplying DNA and tissue. The Mayo Clinic Rochester Cytogenetics Core is thanked for performing the FISH analysis. Finally, the family is thanked for their participation in this study.


  • Frontotemporal dementia
  • Linkage analysis
  • Neuronal intranuclear inclusions
  • Ubiquitin

ASJC Scopus subject areas

  • Clinical Neurology


Dive into the research topics of 'A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17'. Together they form a unique fingerprint.

Cite this