Abstract
Fabry disease (FD) is an X-linked lysosomal rare disease due to a deficiency of α-galactosidase
A activity. The accumulation of glycosphingolipids mainly affects the kidney, heart,
and central nervous system, considerably reducing life expectancy. Although the accumulation
of undegraded substrate is considered the primary cause of FD, it is established that
secondary dysfunctions at the cellular, tissue, and organ levels ultimately give rise
to the clinical phenotype. To parse this biological complexity, a large-scale deep
plasma targeted proteomic profiling has been performed. We analyzed the plasma protein
profiles of FD deeply phenotyped patients (n = 55) compared to controls (n = 30) using
next-generation plasma proteomics including 1463 proteins. Systems biology and machine
learning approaches have been used. The analysis enabled the identification of proteomic
profiles that unambiguously separated FD patients from controls (615 differentially
expressed proteins, 476 upregulated, and 139 downregulated) and 365 proteins are newly
reported. We observed functional remodeling of several processes, such as cytokine-mediated
pathways, extracellular matrix, and vacuolar/lysosomal proteome. Using network strategies,
we probed patient-specific tissue metabolic remodeling and described a robust predictive
consensus protein signature including 17 proteins CD200, SPINT1, CD34, FGFR2, GRN,
ERBB4, AXL, ADAM15, PTPRM, IL13RA1, NBL1, NOTCH1, VASN, ROR1, AMBP, CCN3, and HAVCR2.
Our findings highlight the pro-inflammatory cytokines' involvement in FD pathogenesis
along with extracellular matrix remodeling. The study shows a tissue-wide metabolic
remodeling connection to plasma proteomics in FD. These results will facilitate further
studies to understand the molecular mechanisms in FD to pave the way for better diagnostics
and therapeutics.
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Article info
Publication history
Published online: February 27, 2023
Accepted:
February 21,
2023
Received in revised form:
January 18,
2023
Received:
September 28,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
AVAILABILITY OF DATA: All the data that support the findings are presented in the manuscript and the supplementary material.
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
