From genotype to phenotype: A clinical, pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation
Ziad S. Nasreddine MD
Université de Sherbrooke, Service de Neurologie, Hopital Charles LeMoyne, Greenfield Park, Quebec, Canada
Search for more papers by this authorMaxim Loginov MD
Neurogenetics Program, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Department of Neurology, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Search for more papers by this authorLorraine N. Clark PhD
Department of Neurology, University of California-San Francisco, School of Medicine, San Francisco, CA
Gallo Clinic and Research Center, San Francisco, CA
Search for more papers by this authorJacques Lamarche MD
Département de Pathologie, Centre Universitaire de Santé de l'Estrie, Sherbrooke, Quebec, Canada
Search for more papers by this authorBruce L. Miller MD
Department of Neurology, University of California-San Francisco, School of Medicine, San Francisco, CA
Search for more papers by this authorAlbert Lamontagne MD
Service de Neurologie, Centre Universitaire de Santé de l'Estrie, Sherbrooke, Quebec, Canada
Search for more papers by this authorVictoria Zhukareva PhD
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Search for more papers by this authorVirginia M.-Y. Lee PhD
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Search for more papers by this authorKirk C. Wilhelmsen MD, PhD
Department of Neurology, University of California-San Francisco, School of Medicine, San Francisco, CA
Gallo Clinic and Research Center, San Francisco, CA
Search for more papers by this authorCorresponding Author
Daniel H. Geschwind MD, PhD
Neurogenetics Program, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Department of Neurology, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Neurogenetics Program, Neurology Department, UCLA School of Medicine, 710 Westwood Plaza, RNRC Rm 1-145, Los Angeles, CA 90095-1769Search for more papers by this authorZiad S. Nasreddine MD
Université de Sherbrooke, Service de Neurologie, Hopital Charles LeMoyne, Greenfield Park, Quebec, Canada
Search for more papers by this authorMaxim Loginov MD
Neurogenetics Program, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Department of Neurology, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Search for more papers by this authorLorraine N. Clark PhD
Department of Neurology, University of California-San Francisco, School of Medicine, San Francisco, CA
Gallo Clinic and Research Center, San Francisco, CA
Search for more papers by this authorJacques Lamarche MD
Département de Pathologie, Centre Universitaire de Santé de l'Estrie, Sherbrooke, Quebec, Canada
Search for more papers by this authorBruce L. Miller MD
Department of Neurology, University of California-San Francisco, School of Medicine, San Francisco, CA
Search for more papers by this authorAlbert Lamontagne MD
Service de Neurologie, Centre Universitaire de Santé de l'Estrie, Sherbrooke, Quebec, Canada
Search for more papers by this authorVictoria Zhukareva PhD
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Search for more papers by this authorVirginia M.-Y. Lee PhD
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Search for more papers by this authorKirk C. Wilhelmsen MD, PhD
Department of Neurology, University of California-San Francisco, School of Medicine, San Francisco, CA
Gallo Clinic and Research Center, San Francisco, CA
Search for more papers by this authorCorresponding Author
Daniel H. Geschwind MD, PhD
Neurogenetics Program, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Department of Neurology, University of California-Los Angeles, School of Medicine, Los Angeles, CA
Neurogenetics Program, Neurology Department, UCLA School of Medicine, 710 Westwood Plaza, RNRC Rm 1-145, Los Angeles, CA 90095-1769Search for more papers by this authorAbstract
Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21-22. In this study, linkage analysis was performed in a large pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational analysis of the tau coding region identified a C-to-T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau-positive inclusions that were most prominent in the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick-like bodies and associated granulovacuolar degeneration. These Pick-like bodies were observed in 1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively aggregated in both gray and white matter of affected individuals. Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau-positive inclusions was not identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition. Ann Neurol 1999;45:704–715
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