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Brain Advance Access originally published online on January 9, 2006
Brain 2006 129(4):853-867; doi:10.1093/brain/awh724
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Ian R. Mackenzie1, Matthew Baker6, Gemma West6, John Woulfe4, Najeeb Qadi1,2, Jennifer Gass6, Ashley Cannon6, Jennifer Adamson6, Howard Feldman1,2, Caroline Lindholm1, Stacey Melquist6, Rachel Pettman5, A. Dessa Sadovnick1,2,3, Emily Dwosh1,3, Sidney W. Whiteheart7, Michael Hutton6 and Stuart M. Pickering-Brown8

1 Department of Pathology, 2 Division of Neurology, 3 Department of Medical Genetics, University of British Columbia, Vancouver, 4 Department of Pathology, Ottawa Hospital, Ottawa, Ontario, 5 Department of Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada, 6 Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 7 Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA and 8 Division of Laboratory and Regenerative Medicine, Department of Medicine, University of Manchester, Manchester, UK

Correspondence to: Michael Hutton, PhD, Department of Neuroscience, Mayo Clinic College of Medicine, 4500, San Pablo Road, Jacksonville, FL 32224, USA E-mail: hutton.michael{at}mayo.edu

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-1 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.

Key Words: frontotemporal dementia; ubiquitin; linkage analysis; neuronal intranuclear inclusions

Abbreviations: FTD = frontotemporal dementia; NII = neuronal intranuclear inclusions; NSF = N-ethylmaleimide-sensitive factor; PML = promyelocytic leukaemia protein; ub-ir = immunoreactive for ubiquitin

Received November 4, 2005. Accepted November 28, 2005.


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