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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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Related in: MedlinePlus

Fine mapping haplotype analysis using microsatellite and SNP markers to resolve the position of a meiotic recombination in pedigree member III:8. Four SNPs from representative genes are indicated (rs10812616, rs10812615, rs17769294 and rs10122902 for C9orf11; rs2383768, rs13296489, rs1331870 and rs10968460 for LINGO2; rs2026739, rs3780473, rs10970975 and rs12985 for ACO1; rs10813831, Arg71His, rs17289927 and rs6476363 for DDX8). The informative SNP haplotypes definitively place the recombination breakpoint between D9S1118 and D9S304. The black box indicates the portion of the disease haplotype which is not shared by pedigree member III:8. Transcript map indicating the relative positions of known genes and transcripts (open boxes) (not drawn to scale).
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Figure 4: Fine mapping haplotype analysis using microsatellite and SNP markers to resolve the position of a meiotic recombination in pedigree member III:8. Four SNPs from representative genes are indicated (rs10812616, rs10812615, rs17769294 and rs10122902 for C9orf11; rs2383768, rs13296489, rs1331870 and rs10968460 for LINGO2; rs2026739, rs3780473, rs10970975 and rs12985 for ACO1; rs10813831, Arg71His, rs17289927 and rs6476363 for DDX8). The informative SNP haplotypes definitively place the recombination breakpoint between D9S1118 and D9S304. The black box indicates the portion of the disease haplotype which is not shared by pedigree member III:8. Transcript map indicating the relative positions of known genes and transcripts (open boxes) (not drawn to scale).

Mentions: The 5.9Mb minimal disease region contains 14 known genes as listed by the UCSC Bioinformatics page, consisting of C9orf11 (ACR formation associated factor), MOBKL2B, IFNK, c9orf72, LINGO2, ACO1, DDX58, TOPORS, NDUFB6, TAF1L, APTX, DNAJA1, SMU1, and B4GALT1 (Figure 4). The coding and non-coding exonic sequence and flanking intronic regions of 11 of the initial set of candidate genes (excluding TAF1L, SMU1 and B4GALT1) were screened by direct sequencing of PCR products amplified from genomic template. Screening of the candidate genes detected 42 polymorphisms, of which six were considered novel, including two variants in C9orf11 (IVS1 +33 GT insertion/deletion, IVS4 -44 G/A); three in DDX58 (Arg71His CGT to CAT, IVS16 -23 C/A, IVS16 + 11 G/A) and one in APTX (IVS6 -12 insertion/deletion T). We considered the DDX58 amino acid change to be a polymorphism as it was found in unaffected and aged controls obtained from the Sydney Older Persons Study cohort [30] with a frequency of 0.03.


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)

Fine mapping haplotype analysis using microsatellite and SNP markers to resolve the position of a meiotic recombination in pedigree member III:8. Four SNPs from representative genes are indicated (rs10812616, rs10812615, rs17769294 and rs10122902 for C9orf11; rs2383768, rs13296489, rs1331870 and rs10968460 for LINGO2; rs2026739, rs3780473, rs10970975 and rs12985 for ACO1; rs10813831, Arg71His, rs17289927 and rs6476363 for DDX8). The informative SNP haplotypes definitively place the recombination breakpoint between D9S1118 and D9S304. The black box indicates the portion of the disease haplotype which is not shared by pedigree member III:8. Transcript map indicating the relative positions of known genes and transcripts (open boxes) (not drawn to scale).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Fine mapping haplotype analysis using microsatellite and SNP markers to resolve the position of a meiotic recombination in pedigree member III:8. Four SNPs from representative genes are indicated (rs10812616, rs10812615, rs17769294 and rs10122902 for C9orf11; rs2383768, rs13296489, rs1331870 and rs10968460 for LINGO2; rs2026739, rs3780473, rs10970975 and rs12985 for ACO1; rs10813831, Arg71His, rs17289927 and rs6476363 for DDX8). The informative SNP haplotypes definitively place the recombination breakpoint between D9S1118 and D9S304. The black box indicates the portion of the disease haplotype which is not shared by pedigree member III:8. Transcript map indicating the relative positions of known genes and transcripts (open boxes) (not drawn to scale).
Mentions: The 5.9Mb minimal disease region contains 14 known genes as listed by the UCSC Bioinformatics page, consisting of C9orf11 (ACR formation associated factor), MOBKL2B, IFNK, c9orf72, LINGO2, ACO1, DDX58, TOPORS, NDUFB6, TAF1L, APTX, DNAJA1, SMU1, and B4GALT1 (Figure 4). The coding and non-coding exonic sequence and flanking intronic regions of 11 of the initial set of candidate genes (excluding TAF1L, SMU1 and B4GALT1) were screened by direct sequencing of PCR products amplified from genomic template. Screening of the candidate genes detected 42 polymorphisms, of which six were considered novel, including two variants in C9orf11 (IVS1 +33 GT insertion/deletion, IVS4 -44 G/A); three in DDX58 (Arg71His CGT to CAT, IVS16 -23 C/A, IVS16 + 11 G/A) and one in APTX (IVS6 -12 insertion/deletion T). We considered the DDX58 amino acid change to be a polymorphism as it was found in unaffected and aged controls obtained from the Sydney Older Persons Study cohort [30] with a frequency of 0.03.

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