Brain Advance Access published online on October 9, 2006
Brain, doi:10.1093/brain/awl268
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1 Department of Neurology, Mayo Clinic, Rochester, MN, USA; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA
* To whom correspondence should be addressed. We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G
Received July 31, 2005
Revised August 29, 2006
Accepted August 30, 2006
Article
Frontotemporal dementia and parkinsonism associated with the IVS1+1G
Bradley F. Boeve 1 *, Matt Baker 2, Dennis W. Dickson 3, Joseph E. Parisi 4, Caterina Giannini 5, Keith A. Josephs 1, Michael Hutton 6, Stuart M. Pickering-Brown 2, Rosa Rademakers 2, David Tang-Wai 7, Clifford R. Jack Jr 8, Kejal Kantarci 9, Maria M. Shiung 9, Todd Golde 6, Glenn E. Smith 10, Yonas E. Geda 10, David S. Knopman 1, and Ronald C. Petersen 1
A mutation in progranulin: a clinicopathologic study
2 Neurogenetics Laboratory, Mayo Clinic, Jacksonville, FL, USA
3 Neuropathology Laboratory, Mayo Clinic, Jacksonville, FL, USA; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA
4 Department of Neurology, Mayo Clinic, Rochester, MN, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA
5 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
6 Neurogenetics Laboratory, Mayo Clinic, Jacksonville, FL, USA; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA
7 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
8 Department of Diagnostic Radiology--Neuroradiology, Mayo Clinic, Rochester, MN, USA; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA
9 Department of Diagnostic Radiology--Neuroradiology, Mayo Clinic, Rochester, MN, USA
10 Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA
Bradley F. Boeve, E-mail: bboeve{at}mayo.edu
Abstract 
A) which is predicted to destroy the 5'-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1GA mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease--the ‘hypoprogranulinopathies’.
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