Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

Authors

• Stephanie A. Zlatic, Emory University
• Alysia Vrailas-Mortimer, Illinois State University, University of Denver
• Avanti Gokhale, Emory University
• Lucas J. Carey, Illinois State University
• Elizabeth Scott, Illinois State University
• Reid Burch, Illinois State University, University of Denver
• Morgan M. McCall, Illinois State University
• Samantha Rudin-Rush, Agnes Scott College
• John Bowen Davis, Mercer University School of Medicine
• Cortnie Hartwig, Emory University, Agnes Scott College
• Erica Werner, Emory University
• Lian Li, Emory University
• Michael Petris, University of Missouri
• Victor Faundez, Emory University

Publication Date

1-31-2018

Document Type

Article

Organizational Units

College of Natural Science and Mathematics, Biological Sciences

Keywords

SILAC, Rare disease, Copper, PARK gene, Parkinson, Menkes, ATP7A, UCHL1, Genealogical proteomics, Precision medicine

Abstract

Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A−/y fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical “omics” strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes.

Copyright Date

1-31-2018

Copyright Statement / License for Reuse

All Rights Reserved.

Rights Holder

Elsevier Inc.

Provenance

Received from author

Language

English (eng)

Extent

13 pgs

Publication Statement

Copyright is held by Elsevier Inc. User is responsible for all copyright compliance.

Publication Title

Cell Systems

Volume

6

Issue

3

First Page

368

Last Page

380.e6

ISSN

2405-4720

Recommended Citation

Zlatic, S. A., Vrailas-Mortimer, A., Gokhale, A., Carey, L. J., Scott, E., Burch, R., ..., & Faundez, V. (2018). Rare disease mechanisms identified by genealogical proteomics of copper homeostasis mutant pedigrees. Cell Systems, 6(3), 368–380.e6. DOI: 10.1016/j.cels.2018.01.008

DOI Link

https://doi.org/10.1016/j.cels.2018.01.008