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Author Notes:

Address Correspondence to SZ (szlatic@gmail.com) and VF (vfaunde@emory.edu).

These authors contributed equally: S.A.Z., A.V-M., and A.G.

Conceptualization, V.F., A.V-M., A.G., C.H. and S.Z.

Methodology, V.F., A.V-M., A.G., C.H., and S.Z.

Investigation, A.V-M., A.G., C.H., S.Z., L.J.C; E.S., R.B., S.R-R., J.B.D., M.M. M, and E.W; Writing – Original Draft, V.F; Writing – Review & Editing, V.F., A.V-M., A.G., C.H. and S.Z.; Resources, M.P. and L.L.; Funding Acquisition, Supervision, Formal Analysis, Data curation, and Visualization, V.F.

We are indebted to the Faundez lab members for their comments.

There are no interests to declare by all authors.


Research Funding:

This work was supported by grants from the National Institutes of Health NS088503 and R56 MH111459 to VF, DK093386 to MP, and NS092343 to LL.

SRR was supported by the Goizueta Foundation STEM Success Initiative, the Frances Marx Shillinglaw Women in Science Fund, and the SURE Scholars Program at Emory University.

JBD was supported by the Mattel Initiative.

Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology

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

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Journal Title:

Cell Systems


Volume 6, Number 3


, Pages 368-+

Type of Work:

Article | Post-print: After Peer Review


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. Rare genetic diseases provide fundamental insight into important biological questions and common diseases. Zlatic et al. present a strategy, termed genealogical proteomics, to investigate the molecular manifestations and mechanism of disease by comparing within a family samples from normal and affected subjects. Using this approach, the authors study a rare copper metabolism genetic disorder and find tantalizing connections with molecules and mechanisms known in Parkinson disease. Thus, genealogical proteomics is a promising approach for biological discovery and precision medicine.

Copyright information:

© 2018 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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