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

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.

The A431E mutation in PSEN1 causing Familial Alzheimer’s Disease originating in Jalisco State, Mexico: an additional fifteen families

“…Our independent finding of 15 additional families with autosomal dominant AD associated with the Ala431Glu substitution in PSEN1, all of those in whom the flanking CA and GT repeats were tested having shared alleles, and the fact that nine of these families could trace their roots to Jalisco confirm the findings of Yescas et al [1] regarding a likely founder effect. Furthermore, we extend their observations by showing a higher prevalence of spastic paraparesis and describe an apparently non-Hispanic Caucasian with this mutation.…”

“…We read with interest the article by Yescas et al [1] reporting nine families from Jalisco State in Mexico with early-onset autosomal dominant Alzheimer's Disease (AD), all of whom harbored the Ala431Glu substitution in the PSEN1 gene. The identity of polymorphic dinucleotide polymorphisms flanking this gene in all mutation carriers that was absent in most non-carriers strongly suggests the descent of these persons from a common founder.…”

Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database

“…Twenty percent of the ADAD patients were of Hispanic origin, due largely to the inclusion of 6 persons with the A431E and 6 with the G206A PSEN1 mutation, which represent founder effects arising from Jalisco, Mexico (29, 30), and Puerto Rico (31), respectively. Persons of Hispanic origin are underrepresented in the NACC; thus, we were unable to match the groups perfectly with respect to ethnicity; however, no statistically significant difference between groups with respect to ethnicity was present.…”

Cortical and Hippocampal Atrophy in Patients with Autosomal Dominant Familial Alzheimer’s Disease

“…There were 33 nondemented and 3 demented subjects from 10 families with PSEN1 mutations and 2 families with V717I APP mutation. The 10 PSEN1 families included 1 with L235V [12], 1 with G206A [13], and 7 with A431E substitution (founder effect originating in Jalisco State in Mexico [14,15]). Subjects who tested positive for the mutation will be referred to as carriers and subjects who tested negative for the mutation will be referred to as controls.…”