RESUMO
BACKGROUND: This study investigates the association between TOMM40 poly-T length, age at onset, and neuropathology in individuals with Alzheimer's disease (AD) with the apolipoprotein E (APOE) ε3/ε3 allele. METHODS: Thirty-two presenilin 1 (PSEN1) mutation carriers with AD, 27 presenilin 2 (PSEN2) mutation carriers with AD, 59 participants with late-onset AD (LOAD), and 168 autopsied subjects from a community-based cohort were genotyped for TOMM40 intron 6 poly-T (rs10524523) length using short tandem repeat assays. RESULTS: Among AD individuals with PSEN2 mutations, the presence of a long poly-T was associated with an earlier age at onset, whereas there were no such associations for subjects with PSEN1 mutations or LOAD. In community-based participants, the presence of a long poly-T was associated with increased neuritic tangles and a greater likelihood of pathologically diagnosed AD. CONCLUSION: TOMM40 intron 6 poly-T length may explain some of the variation in age at onset in PSEN2 familial AD and may be associated with AD neuropathology in persons with APOE ε3/ε3.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E3/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana Transportadoras/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Mutação , Poli T/genética , Presenilina-1/genética , Presenilina-2/genéticaRESUMO
A 49-year-old Korean male patient with dementia was diagnosed with probable early-onset Alzheimer's disease (AD). He presented with memory problems, personality changes, and disorientation. His family history of dementia was probably negative, since no family member with dementia was found or mentioned. Mild cortical atrophy was observed upon magnetic resonance imaging analyses of his brain, and the single-photon emission computed tomography analysis revealed hypoperfusion in the frontal, temporal, and limbic lobes. The patient was tested for mutations in APP, PSEN1, PSEN2, PGRN, MAPT, and PRNP genes. Genetic analysis revealed R62C mutation in PSEN2 gene. PSEN2 R62C mutation was previously reported in European populations, including Dutch and Belgian families with AD. Herein, we present the first case report of PSEN2 R62C mutation in Asia. PolyPhen-2 and SIFT software analyses predicted this mutation as "possibly damaging", suggesting its potential involvement with AD. In silico protein structural prediction analyses of PSEN2 R62 and C62 revealed two divergent structures, suggesting that large perturbations of R62C mutation might cause dysfunctions of PSEN2, which may alter the normal amyloid production.
Assuntos
Doença de Alzheimer/genética , Presenilina-2/genética , Ásia , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Mutations in the gene PSEN2 are a rare cause of early onset Alzheimer's disease (EOAD). PSEN2 sequence variants are often only found in one patient and pathogenicity cannot be formally documented. Here we describe a previously unrecognized sequence change (c.376G>A) in PSEN2 in an EOAD patient and her likewise affected mother. This change results in the exchange of amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). Pathogenicity of the mutation is shown by segregation with disease, evolutionary conservation of E126, and in silico analysis of the mutation.