SORL1 mutations in early- and late-onset Alzheimer disease

摘要

Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor ( SORL1 ) gene. Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations. Results: SORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking. Conclusions: The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation. Alzheimer disease (AD) is the leading cause of dementia in the elderly. 1 Multiple genes have been implicated in risk for both late-onset Alzheimer disease (LOAD; onset >65 years of age) and early-onset Alzheimer disease (EOAD; onset 2 including the sortilin-related receptor ( SORL1 ) gene. Located on chromosome 11q23.2-q24.2, SORL1 influences the differential sorting of the amyloid precursor protein (APP) and regulation of β-amyloid (Aβ) production, making it biologically plausible for AD risk. 3 , – 9 Compelling evidence for the involvement of SORL1 in AD comes from a large meta-analysis of >30,000 individuals, which confirmed that variants in SORL1 are associated with AD risk. 10 Furthermore, whole-exome sequencing (WES) has identified potentially damaging SORL1 mutations in patients with both EOAD and LOAD. 11 , 12 Of note, a WES study of a large EOAD cohort found a greater frequency of predicted damaging missense SORL1 variants in cases vs controls, with this effect enriched among cases with a positive family history. 13 Clearly, rare coding variants in SORL1 are tied to risk for EOAD and LOAD. Finally, while SORL1 mutations have been reported in multiple patients with AD, there has been little investigation of clinical phenotypes beyond dementia and age at onset (AAO) among these individuals. For this study, we examined well-characterized EOAD families using WES to discover AD risk genes. Our efforts focused on clinical characterization of individuals with SORL1 alterations and investigation of the functional effect of the identified SORL1 alterations in a series of gene overexpression experiments.