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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the most common form of dementia in the elderly, which mainly characterized by the progressive decline in memory and cognitive function
The vast majority of AD occur on a sporadic basis, mutations in three genes [amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2)] could lead to rare familial AD (FAD;
Patients carrying with pathogenic genes of AD (APP, PSEN1, PSEN2) and vascular cognitive impairment [notch receptor 3 (NOTCH3), HtrA serine peptidase 1 (HTRA1), collagen type IV alpha 1 chain (COL4A1), three prime repair exonuclease 1 (TREX1), galactosidase alpha (GLA)] were excluded
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the most common form of dementia in the elderly, which mainly characterized by the progressive decline in memory and cognitive function. There are four genes, which were gelsolin (GSN), cystatin C (CST3), transthyretin (TTR), and integral membrane protein 2B (ITM2B), whose mutations can lead to autosomal dominant HA, while playing an important role in the pathogenesis of AD (Ray et al, 2000; Sastre et al, 2004; Hirko et al, 2007; Mi et al, 2007; Buxbaum et al, 2008; Buxbaum and Johansson, 2017; Tamayev et al, 2011; Matsuda and Senda, 2019). They all could play as physiological inhibitors of Aβ under specific conditions, which might be associated with AD
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