Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer’s Disease

Abstract

Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer's disease (AD). Mutations of gelsolin (GSN), cystatin C (CST3), transthyretin (TTR), and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD. Genes targeted sequencing (GTS), including GSN, CST3, TTR, and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China. As a result, according to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame-shift mutations (GSN:c.1036delA:p.K346fs and GSN:c.8_35del:p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β-amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while the other four patients with P3fs mutation had a late onset [(Mean ± SD): 69.50 ± 5.20 years] and a long course of illness [(Mean ± SD): 9.24 ± 4.86 years]. Besides, we also discovered 17 variants of uncertain significance (VUS) in these four genes. To our knowledge, we are the first to report AD phenotype with GSN mutations in patients with AD in the Chinese cohort. Although mutations in the GSN gene are rare, it may explain a small portion of clinically diagnosed AD.

The role of vascular dementia associated genes in patients with Alzheimer's disease: A large case–control study in the Chinese population

“… 60 Interestingly, our previous study demonstrated that mutations in GSN may contribute to the pathogenesis of AD. 22 This present study revealed that variants in GSN were suggestively correlated not only with AAO but also with MMSE scores, further implicating the GSN gene in AD development. ITM2B gene encodes integral membrane protein 2B, which can interact with Aβ‐precursor protein and inhibit its processing.…”

“…Eight VaD‐associated genes, NOTCH3 , HTRA1 , TREX1 , GLA , COL4A1 , CST3 , GSN , and ITM2B , were finally seclected. 18 , 19 , 20 , 21 , 22 …”

Genetic effect of MTHFR C677T, A1298C, and A1793G polymorphisms on the age at onset, plasma homocysteine, and white matter lesions in Alzheimer's disease in the Chinese population

“…Blood samples (10 mL per subject) were obtained by venipuncture from each subject and transferred to ethylenediaminetetraacetic acid (EDTA) tubes. Genomic DNA was isolated from peripheral blood leukocytes using a standard protocol [ 17 ]. All isolated DNA samples were measured for quality and quantity by a fluorometer and normalized to 50 ng/μL.…”

GSNgene frameshift mutations in Alzheimer’s disease

“…Moreover, frameshift mutations in the GSN gene in patients with AD were only observed in Han populations. Among the reported mutations in the GSN gene, there are three frameshift mutations (A34fs, K346fs and P3fs8 26), all of which were reported in Han populations, suggesting geographical heterogeneity of the GSN mutations. For missense variants, we failed to identify significant enrichment of these missense variants across the GSN gene in patients with AD compared with the controls.…”

“…The well-known pathogenic missense mutations of the GSN gene have been reported to be associated with familial amyloidosis of the Finnish type (FAF), which mainly manifests as corneal lattice dystrophy, cranial neuropathy, peripheral neuropathy and cutis laxa 7. Recently, we reported patients with GSN frameshift mutations were characterised by the typical AD phenotype 8. Among the five patients with AD (cases 1–5) with GSN frameshift mutations, unfortunately, only the patient with the K346fs mutation (case 1) accepted Pittsburgh compound ([ 11 C]PIB)positron emission tomography (PET) examination and was confirmed to have cerebral Aβ deposition; however, no patient agreed to undergo skin biopsy, which is of great help in differentiating the diagnosis of FAF 8.…”