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Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer’s disease in Mexican families

Departamento de Neurogenética y Biología Molecular, lnstituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, México D.F., México.
Neurogenetics (Impact Factor: 2.66). 08/2006; 7(3):195-200. DOI: 10.1007/s10048-006-0043-3
Source: PubMed

ABSTRACT The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.

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    • "Subjects Subjects came from 8 families: 2 families had the V717I substitution in APP (Mullan et al. 1993), 1 the L235V substitution in PSEN1, and 5 had the A431E substitution in PSEN1, representing a founder effect (Murrell et al. 2006; Yescas et al. 2006). Mean age of symptom onset among families ranged from 36 to 49 years. "
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