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SORL1 mutations in early- and late-onset Alzheimer disease.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Cuccaro, Michael L 
Carney, Regina M 
Zhang, Yalun 
Bohm, Christopher 
Kunkle, Brian W 

Abstract

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.

Description

Keywords

1109 Neurosciences, Biomedical, Basic Science, Human Genome, Alzheimer's Disease, Clinical Research, Dementia, Brain Disorders, Neurodegenerative, Aging, Genetics, Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurological, 2.1 Biological and endogenous factors

Journal Title

Neurol Genet

Conference Name

Journal ISSN

2376-7839
2376-7839

Volume Title

2

Publisher

Ovid Technologies (Wolters Kluwer Health)

Rights

All rights reserved
Sponsorship
Wellcome Trust (081864/Z/06/Z)