GSNgene frameshift mutations in Alzheimer’s disease

Abstract

BackgroundThe pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identifiedGSNframeshift mutations existed in patients with Alzheimer’s disease (AD). TheGSNgenotype–phenotype heterogeneity and the role ofGSNframeshift mutations in patients with AD are unclear.MethodIn total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects ofGSNmutations were evaluated in vitro. GSN, Aβ42, Aβ40 and Aβ42/40 were detected in both plasma and cerebrospinal fluid (CSF).ResultsSix patients with AD withGSNP3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD withGSNframeshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to theGSNloss of function in inhibiting Aβ-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aβ42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline.ConclusionsGSNframeshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.