Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7:43-51

Laboratory of Neurogenetics, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Biochemistry, Antwerpen, Belgium.
Human Molecular Genetics (Impact Factor: 6.68). 02/1998; 7(1):43-51. DOI: 10.1093/hmg/7.1.43
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ABSTRACT Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.

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Available from: Christine Van Broeckhoven, Aug 20, 2015
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    • "with a probable deleterious effect . It clusters on the alpha helix surface of the fifth transmembrane domain ( TM5 ) , corresponds to a conserved residue among different species and in PSEN1 ( p . A231 ) , where 2 causative mutations ( p . A231V and p . A231T ) have been described in a Dutch , French and Canadian family ( Campion et al . , 1999 ; Cruts et al . , 1998 ; Rogaeva et al . , 2001 ) . The patient carrying the p . A237V variant was diagnosed at 87 years , homozygous for APOE ε3 allele , and did not refer any family history of AD ."
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    • "Notably, the clinical presentation of familial forms of AD (FAD) is more complex, and mutations of the presenilin 1 (PSEN-1, at locus 14q24.3), presenilin 2 (PSEN-2, at locus 1q31-q42) and amyloid precursor protein (APP, at locus 21q21.2) have also been described in these patients (Cruts et al. 1998; Goate et al. 1991). On the basis of their function, these proteins regulate the production of the amyloid b-(Ab) peptide by an elusive mechanism that modulates the proteolysis of APP, but how these elements orchestrate the overall activity is still a matter of investigation. "
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