تشخیص جهش های ژن در بیماران ژاپنی آلزایمر توسط تعیین توالی نیمه رسانا

Alzheimer's disease (AD) is the most common form of dementia. To date, several genes have been identified as the cause of AD, including PSEN1, PSEN2, and APP. The association between APOE and late-onset AD has also been reported. We here used a bench top next-generation sequencer, which uses an integrated semiconductor device, detects hydrogen ions, and operates at a high-speed using nonoptical technology. We examined 45 Japanese AD patients with positive family histories, and 29 sporadic patients with early onset (<60-year-old). Causative mutations were detected in 5 patients in the familial group (11%). Three patients had a known heterozygous missense mutation in the PSEN1 gene (p.H163R). Two patients from 1 family had a novel heterozygous missense mutation in the PSEN1 gene (p.F386L). In the early onset group, 1 patient carrying homozygous APOEε4 had a novel heterozygous missense mutation in the PSEN2 gene (p.T421M). Approximately 43% patients were APOEε4 positive in our study. This new sequencing technology is useful for detecting genetic variations in familial AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amnesia, poor judgment, impaired visuospatial abilities or language functions, and changes in personality. (McKhann et al., 2011) Neuronal loss, senile plaques, and neurofibrillary tangles are the pathologic hallmarks of AD. To date, several genes have been identified as the cause of AD, including PSEN1 (MIM 104311) ( Sherrington et al., 1995), PSEN2 (MIM 600759) ( Levy-Lahad et al., 1995), and APP (MIM 104760) ( Goate et al., 1991). These genes are involved in the amyloid-beta pathway, and have been included as causative genes in the new diagnostic guidelines for AD ( Jack et al., 2011). PSEN1 mutations are the most frequent, whereas PSEN2 mutations are very rare. The presenilin 1 and 2 proteins are components of the γ secretase complex. APP encodes the amyloid precursor protein, and mutations are mainly adjacent to the ß and γ secretase cleavage site ( Cohn-Hokke et al., 2012). APOE (MIM 107741) has also been associated with late onset AD because the frequency of APOEε4 allele was found to be high in these patients ( Saunders et al., 1993). APOE was proposed to be a moderately penetrant gene with semi-dominant inheritance ( Genin et al., 2011). Until recently, these genes were screened using Sanger sequencing. However, Sanger sequencing is time-consuming and costly; therefore, it is not ideal for routine diagnostic purposes. Over the past few years, high-throughput genome technologies have changed the genetic landscape of AD (Bettens et al., 2013). We used ion-sequencing technology in the present study. Ion sequencing uses an integrated semiconductor device to detect hydrogen ions and operates at high-speed using nonoptical technology. We also assessed the disadvantages of this technology.