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P3–170: The influence of the APOE gene on life expectancy
Author(s) -
Rosvall Lina,
Rizzuto Debora,
Graff Caroline,
Fratiglioni Laura
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1438
Subject(s) - apolipoprotein e , life expectancy , dementia , proportional hazards model , gerontology , context (archaeology) , allele , hazard ratio , genotype , disease , population , medicine , longitudinal study , survival analysis , demography , psychology , genetics , biology , confidence interval , gene , pathology , environmental health , paleontology , sociology
suppression of DNA recombination. The tau gene (MAPT) resides within the inversion and tau dysfunction has been shown to play a central role in many neurodegenerative diseases. Chromosomal imbalance is often associated with learning disability, dysmorphism, congenital abnormalities and abnormalities of growth. A deletion at 17q21.31 was identified in a 17 year old boy with severe learning disability by array-CGH (array-comparative genomic hybridization). Subsequent array-CGH studies have identified two more patients of similar phenotype with deletions essentially identical in size and of same the genomic position. Objective(s): For each index case and unaffected parents we have performed in-depth haplotype analysis of the deletion and flanking regions in respect of H1 and H2. Methods: The presence of DNA copy number changes was investigated by array-CGH, employing a DNA microarray constructed from large insert clones spread at approximately 1 Mb intervals across the genome and a dense-tiling fosmid array of 350 clones representing 2 Mb of sequence that includes the inversion of the MAPT region. Haplotypes within each triad at 17q21.31 were constructed using H1/H2 specific single nucleotide polymorphisms (SNPs). Results: Fluorescence in situ hybridization (FISH) experiments sized the deletion to 400 kb and studies in the parents indicated that this event was de novo and therefore the likely underlying cause of the patient’s phenotype. Extended haplotype analysis of the triads traced parental origin of the event to heterozygote carriers of the inversion. A deleted chromosome in one proband was uniquely composed of both H1 and H2 segments, thus documenting a recombination event between the inverted haplotypes. Conclusions: We propose a mechanism for this novel genomic deletion disorder whereby excision occurs between tandem low-copy repeats (LCR) flanking the deleted region on the H2 background, initiated by DNA recombination between inverted segments of H1 and H2. These data further demonstrate the inherent genomic instability at 17q21.31 and raise the possibility that multiplications of the MAPT locus could occur by a similar mechanism.