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: 2.88). 08/2006; 7(3):195-200. DOI: 10.1007/s10048-006-0043-3
Source: PubMed


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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Available from: Marisol López, Jan 13, 2015
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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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    ABSTRACT: Prior functional magnetic resonance imaging (fMRI) studies have found increased activity-related blood oxygen level-dependent (BOLD) signal in cognitively normal persons at genetic risk for Alzheimer's disease (AD). This has been interpreted as a compensatory response to incipient AD pathology. We studied the effects of fully penetrant familial Alzheimer's disease (FAD) mutations and apolipoprotein E (APOE) genotype on BOLD fMRI during a novelty encoding task in presymptomatic subjects. Twenty-three Mexican or Mexican-American persons at-risk for inheriting FAD mutations performed a block design novelty encoding task, and activation exhibited by FAD mutation carriers (MCs) was contrasted with that of noncarriers (NCs) and among APOE genotype groups. FAD MCs (n = 14) showed decreased BOLD activation in the anterior cingulate gyrus relative to 9 NCs. No increased activation was seen in MCs relative to NCs. Four APOE ε3/4 carriers demonstrated increased BOLD signal compared with 14 ε3/3 carriers in the occipital and perisylvian cortices bilaterally. There were no areas where ε3/3 carriers activated more than ε3/4 carriers. Our findings of increased fMRI activation associated with APOE genotype but not with FAD mutations suggest that APOE exerts an effect on the BOLD signal that is not readily explained as a compensatory phenomenon.
    Cerebral Cortex 04/2011; 21(4):877-83. DOI:10.1093/cercor/bhq158 · 8.67 Impact Factor
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    • "The California study groups were comprised of 7 subjects carrying the FAD-associated PSEN1 A431E mutation, 12 patients with SAD and 17 healthy controls (Table 1). The A431E mutation in persons of Mexican origin represents a founder effect arising from Jalisco State [17,18]. This mutation causes an aggressive form of AD with a mean age of onset in the early 40's that is sometimes associated with spastic tetraparesis and "cotton-wool" amyloid plaques on pathology [19]. "
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    ABSTRACT: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39. SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.
    Molecular Neurodegeneration 01/2010; 5(1):2. DOI:10.1186/1750-1326-5-2 · 6.56 Impact Factor
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    ABSTRACT: Nine families with autosomal dominant Alzheimer's disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin.
    Neurogenetics 12/2006; 7(4):277-9. DOI:10.1007/s10048-006-0053-1 · 2.88 Impact Factor
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