Identification and functional characterization of rare variants in DNAJC5/CSP gene associated with Alzheimer Disease

2014 Pilot Project Read More


Principal Investigators: Carlos Cruchaga (WashU Psychiatry) and Bruno Benitez (WashU Medicine)


Our long-term goal is to discover low frequency and rare genetic coding variants (changes in a DNA sequence found in less that one percent of the general population) associated with an increased risk of developing Alzheimer’s Disease (AD).  The cumulative effect of rare variants is very significant in complex disease, as shown by our discovery of rare variants in the Phospholipase D family, member 3 (PLD3) gene  in families with AD.  Additionally, rare variants contribute to a better understanding of the pathobiology of disease.  Rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) revealed novel avenues towards the role of neuroinflamation in AD, and mutations in the amyloid-beta precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes were originally found in rare and phenotypically extreme AD cases.  We recently found that the DNAJC5 gene (DnaJ (Hsp40) homolog, subfamily C, member 5) is a Mendelian dementia-causing gene of an early-onset and rare form of dementia.  In this project, our aim is to identify rare genetic variants in DNAJC5, and to determine whether those rare variants play a role in the risk for AD.   We will do this by combining targeted-pooled-DNA next-generation sequencing in large case-control samples and analysis of Illumina Exome Chip technology, whole-exome sequencing and whole-genome-sequencing data. We will then validate the best candidate variants’s role in amyloidogenesis using in vitro assays and cell model systems.

Grants and Awards

“Effect of mutant DNACJ5/CSPα on lysosomal function in human induced pluripotent stem cell (iPSC)-derived neurons”
Children’s Discovery Institute hPSC Core Pilot Grant Program, Washington University in St. Louis (PI, Benitez).


Benitez BA, Cairns NJ, Schmidt RE, Morris JC, Norton JB, Cruchaga C, Sands MS.Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. Acta Neuropathol Commun; 3:73, (2015).

Benitez BA, Sands MS. Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult-onset neuronal ceroid lipofuscinosis. Sci Rep (7) Article Number: 6332, (2017).

Updated January 2019

Hope Center Investigators

Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.

Carlos Cruchaga


This pilot project is made possible by the Danforth Foundation Challenge.

Danforth Challenge