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Int. J. Mol. Sci. 2018, 19(7), 2026; https://doi.org/10.3390/ijms19072026

Phosphokinome Analysis of Barth Syndrome Lymphoblasts Identify Novel Targets in the Pathophysiology of the Disease

1
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
2
Diabetes Research Envisioned and Accomplished in Manitoba (DREAM), Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
3
Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, MB R3E 3P4, Canada
4
Clinical Research Unit, Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
5
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada
6
Physiology and Pathophysiology, University of Manitoba, St. Boniface Hospital Research Center, Winnipeg, MB R2H 2A6, Canada
7
Center for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
*
Author to whom correspondence should be addressed.
Received: 13 June 2018 / Revised: 6 July 2018 / Accepted: 9 July 2018 / Published: 12 July 2018
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
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Abstract

Barth Syndrome (BTHS) is a rare X-linked genetic disease in which the specific biochemical deficit is a reduction in the mitochondrial phospholipid cardiolipin (CL) as a result of a mutation in the CL transacylase tafazzin. We compared the phosphokinome profile in Epstein-Barr-virus-transformed lymphoblasts prepared from a BTHS patient with that of an age-matched control individual. As expected, mass spectrometry analysis revealed a significant (>90%) reduction in CL in BTHS lymphoblasts compared to controls. In addition, increased oxidized phosphatidylcholine (oxPC) and phosphatidylethanolamine (PE) levels were observed in BTHS lymphoblasts compared to control. Given the broad shifts in metabolism associated with BTHS, we hypothesized that marked differences in posttranslational modifications such as phosphorylation would be present in the lymphoblast cells of a BTHS patient. Phosphokinome analysis revealed striking differences in the phosphorylation levels of phosphoproteins in BTHS lymphoblasts compared to control cells. Some phosphorylated proteins, for example, adenosine monophosphate kinase, have been previously validated as bonafide modified phosphorylation targets observed in tafazzin deficiency or under conditions of reduced cellular CL. Thus, we report multiple novel phosphokinome targets in BTHS lymphoblasts and hypothesize that alteration in the phosphokinome profile may provide insight into the pathophysiology of BTHS and potential therapeutic targets. View Full-Text
Keywords: cardiolipin; Barth Syndrome; phosphokinome; phosphoproteins; rare genetic disease; phospholipid; human lymphoblasts; mitochondria; cardiomyopathy; neutropenia cardiolipin; Barth Syndrome; phosphokinome; phosphoproteins; rare genetic disease; phospholipid; human lymphoblasts; mitochondria; cardiomyopathy; neutropenia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Agarwal, P.; Cole, L.K.; Chandrakumar, A.; Hauff, K.D.; Ravandi, A.; Dolinsky, V.W.; Hatch, G.M. Phosphokinome Analysis of Barth Syndrome Lymphoblasts Identify Novel Targets in the Pathophysiology of the Disease. Int. J. Mol. Sci. 2018, 19, 2026.

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