Association between HFE 187 C>G (H63D) mutation and early-onset familial Alzheimer’s disease PSEN-1 839A>C (E280A) mutation

Abstract

Dear Editor, Alzheimer’s disease (AD, OMIM#104300) is a progressive neurodegenerative disorder characterized by memory loss and cognitive and behavioral abilities impairment. At least three genes have consistently been associated with familial AD (FAD): Aβ precursor protein (APP, OMIM#104760), presenilin-1 (PSEN-1, OMIM#104311) and presenilin-2 (PSN2, OMIM#600759). Noticeably, a single base pair change from A to C (c.839A>C) at codon 280 (gAa-gCa) which results in a Glu-to-Ala substitution in PSEN-1 causes FAD in a large Colombian population in Antioquia region, northwest Colombia [1]. Given that this community is a genetic isolate population [2], this population is a unique resource for the study of modifier genes. Hereditary hemochromatosis (HH, OMIM#235200) is an autosomal recessive disorder of excessive iron uptake and deposition and damage to several organs of the body. HH is most often caused by at least two missense mutations in the gene HFE (chromosome 6p21.3): the c.C187G mutation of exon 2, which results in H63D change at protein translation; and the c.G845A mutation of exon 4, which results in C282Y. Interestingly, brains from AD patients have shown accumulation of iron [3]. Consequently, it is reasonable to think that HFE mutations may be pathological mediator of AD by contributing to brain iron deposition and/or earlier manifestation of dementia symptoms in AD patients. The aim of this study was to examine the allele frequencies of HFE mutations (H63D, C282Y) and their influence on the age of disease onset in a group of patients affected by FAD bearing the E280A mutation in PSEN-1 gene. This investigation was approved by the Ethical Committee of the University of Antioquia (Colombia), and it was supported by Colciencias grants #1115-041-8113 to CVP. A total of 105 individuals (67 women, 38 men) previously genotyped as E280A in PSEN-1 and 220 (117 women, 103 men, range age 18–65 years) non-demented controls, not relatives of FAD patients, were screened for H63D and C282Y in HFE gene by polymerase chain reaction method using the primers sequences reported elsewhere. Amplification mixtures were digested with Mbo I (exon 2) and Rsa I (exon 4) and subsequently analyzed by restriction fragment length polymorphism. Given that the age at onset FAD data (defined as the age at which the patient presented with memory impairment that interferes notably with daily activities) was only available from 75 individuals (52 women, 23 men; mean age of onset at 44.30±5.13; range 33–55 years), they were selected for associative studies between FAD PSN-1 and HH mutations. Tables 1 and 2 show the results of genotype and allelic analysis, respectively. Of notice, the H63D genotype frequencies of healthy normal individuals and FAD patients displayed almost identical distributions for the wild-type, heterozygous, and homozygous conditions [χ(2)=0.43, p=0.8061]. This genotype in both cohorts was at Hardy–Weinberg equilibrium. Similarly, there were no statistically significant differences in the allele frequencies between FAD patients and controls who were wild-type, heterozygous, and homozygous for the H63D alteration [χ(1)=0.39, p=0.5319]. In contrast, there were neither homozygote nor heterozygous for the C282Y mutation in the cohort of FAD patients, and one heterozygote was found among the control group. Given that neither the genotype nor the allelic frequencies of Ann Hematol (2008) 87:671–673 DOI 10.1007/s00277-008-0467-y