Background: Frontotemporal dementia (FTD) has been recognized as one of major forms of non-Alzheimer dementia. Most cases are sporadic. Familial case are reported and mutations in tau have been discovered (FTDP-17). The clinical phenotype of FTDP-17 is broad and often shows overlapping features with other neurodegenerative disorders, such as PSP and Pick’s disease. Screening of tau mutations would be necessary to establish the genotype–phenotype correlations in FTD. Exclusion of linkage to FTDP-17 locus will encourage geneticists to find a new locus for FTD. Objective: To determine the frequency of tau mutations in FTD and related dementia. Methods: A total 27 familial cases of FTD from Italy and North/South Amer- ica participated in the study. Pathological findings were available in seven out of 27 familial cases. We also included 56 cases of FTD and related de- mentia disorders without apparent family history. The brain expressed exons were analyzed by PCR-direct sequencing. A linkage study was performed in a large Italian FTD family at the three loci, chromosome 17q21–22, chromo- some 3 (D3S1284 and D3S1603) and chromosome 9q21–q22. Results: One missense mutation (codon 301 Proline to Leucine) and two splice site muta- tions (+14 and +16 bp downstream exon 10) were identified in four out of 27 familial cases (14.8%). One missense mutation (codon 342 glycine to argi- nine) was identified in the case of early-onset Pick’s disease without family history. The linkage study did not show any evidence of linkage to the three loci. Conclusions: Our study demonstrated low frequency of tau mutations in familial FTD. The absence of linkage may suggest other possible genetic factors related to FTD. In combination with previous screening of the tau gene, the disease-causing mutations may be clustered at exons 9, 10, 12, 13 and the splice site downstream exon 10. The mutation at codon 342 was previ- ously reported in Pick’s disease, which may be unique genotype–phenotype correlation.
Low frequency of tau mutations and further genetic heterogeneity in FTD
RAINERO, Innocenzo;PINESSI, Lorenzo;
2002-01-01
Abstract
Background: Frontotemporal dementia (FTD) has been recognized as one of major forms of non-Alzheimer dementia. Most cases are sporadic. Familial case are reported and mutations in tau have been discovered (FTDP-17). The clinical phenotype of FTDP-17 is broad and often shows overlapping features with other neurodegenerative disorders, such as PSP and Pick’s disease. Screening of tau mutations would be necessary to establish the genotype–phenotype correlations in FTD. Exclusion of linkage to FTDP-17 locus will encourage geneticists to find a new locus for FTD. Objective: To determine the frequency of tau mutations in FTD and related dementia. Methods: A total 27 familial cases of FTD from Italy and North/South Amer- ica participated in the study. Pathological findings were available in seven out of 27 familial cases. We also included 56 cases of FTD and related de- mentia disorders without apparent family history. The brain expressed exons were analyzed by PCR-direct sequencing. A linkage study was performed in a large Italian FTD family at the three loci, chromosome 17q21–22, chromo- some 3 (D3S1284 and D3S1603) and chromosome 9q21–q22. Results: One missense mutation (codon 301 Proline to Leucine) and two splice site muta- tions (+14 and +16 bp downstream exon 10) were identified in four out of 27 familial cases (14.8%). One missense mutation (codon 342 glycine to argi- nine) was identified in the case of early-onset Pick’s disease without family history. The linkage study did not show any evidence of linkage to the three loci. Conclusions: Our study demonstrated low frequency of tau mutations in familial FTD. The absence of linkage may suggest other possible genetic factors related to FTD. In combination with previous screening of the tau gene, the disease-causing mutations may be clustered at exons 9, 10, 12, 13 and the splice site downstream exon 10. The mutation at codon 342 was previ- ously reported in Pick’s disease, which may be unique genotype–phenotype correlation.
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