1. Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9.
- Author
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Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, and Schofield PR
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Australia, Autopsy, Brain metabolism, Brain pathology, Chromosomes, Human, Pair 9 genetics, DNA-Binding Proteins metabolism, Dementia metabolism, Dementia pathology, Family Health, Genetic Linkage, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Haplotypes, Humans, Immunohistochemistry, Microsatellite Repeats genetics, Motor Neuron Disease metabolism, Motor Neuron Disease pathology, Motor Neurons pathology, Pedigree, Polymorphism, Single Nucleotide, Retrospective Studies, Ubiquitin metabolism, tau Proteins metabolism, DNA-Binding Proteins genetics, Dementia genetics, Motor Neuron Disease genetics, Motor Neurons metabolism
- Abstract
Background: Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND., Methods: Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing., Results: Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree., Conclusion: Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.
- Published
- 2008
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