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Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9.

Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR - BMC Neurol (2008)

Bottom Line: 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.This provides the highest reported LOD scores from a single FTLD-MND pedigree.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Prince of Wales Medical Research Institute, Sydney, NSW, Australia. a.luty@powmri.edu.au

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.

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Diagram of chromosome 9p-linked families with FTLD-MND.
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Figure 5: Diagram of chromosome 9p-linked families with FTLD-MND.

Mentions: We re-analysed our linkage data with the phenotype of III:8 altered to an unaffected status using the same autosomal dominant inheritance model (Table 2). Again, only a single locus achieved a significant two-point LOD score of 3.24 at the marker D9S1817. The flanking markers, D9S1845 and D9S1805 also achieved positive LOD scores of 2.90 and 2.46, respectively (Table 2). A multi-point LOD score of 3.41 was observed at marker D9S1817. From the haplotype analysis (Figure 1), a new extended disease haplotype was defined using the distal telomeric meiotic cross-over between markers D9S175 and D9S167 (Figure 1) as identified in seven affected individuals II:2, III:2, III:3, III:5, III:6, III:7 and IV:1. The disease haplotype spans 57 Mb (34 cM) on chromosomal region 9p21-9q12. This region overlaps the three previously reported FTLD-MND regions on chromosome 9p (Figure 5). The recombination breakpoint observed in this study at D9S169 narrows the telomeric boundary of the combined published minimal disease region by 1.1 Mb.


Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9.

Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR - BMC Neurol (2008)

Diagram of chromosome 9p-linked families with FTLD-MND.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2553097&req=5

Figure 5: Diagram of chromosome 9p-linked families with FTLD-MND.
Mentions: We re-analysed our linkage data with the phenotype of III:8 altered to an unaffected status using the same autosomal dominant inheritance model (Table 2). Again, only a single locus achieved a significant two-point LOD score of 3.24 at the marker D9S1817. The flanking markers, D9S1845 and D9S1805 also achieved positive LOD scores of 2.90 and 2.46, respectively (Table 2). A multi-point LOD score of 3.41 was observed at marker D9S1817. From the haplotype analysis (Figure 1), a new extended disease haplotype was defined using the distal telomeric meiotic cross-over between markers D9S175 and D9S167 (Figure 1) as identified in seven affected individuals II:2, III:2, III:3, III:5, III:6, III:7 and IV:1. The disease haplotype spans 57 Mb (34 cM) on chromosomal region 9p21-9q12. This region overlaps the three previously reported FTLD-MND regions on chromosome 9p (Figure 5). The recombination breakpoint observed in this study at D9S169 narrows the telomeric boundary of the combined published minimal disease region by 1.1 Mb.

Bottom Line: 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.This provides the highest reported LOD scores from a single FTLD-MND pedigree.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Prince of Wales Medical Research Institute, Sydney, NSW, Australia. a.luty@powmri.edu.au

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.

Show MeSH
Related in: MedlinePlus