MSACL 2019 EU Abstract

Self-Classified Topic Area(s): Metabolites & Metabolomics

Untargeted Metabolomic Profiling of Plasma Samples of Patients with MBOAT7 Gene Defect

Basri Gülbakan (1), Hande Akar (2), Didem Yücel‐Yılmaz (1), Rıza Köksal Özgül (1), Dilek Yalnızoğlu (3), Bekir Salih (2), Ali Dursun (4)
(1) Hacettepe University, Institute of Child Health, Ankara, Turkey; (2) Hacettepe University, Deparment of Chemistry Ankara, Turkey; (3) Hacettepe University, Faculty of Medicine, Department of Pediatrics, Division of Neurology, Ankara, Turkey; (4) Hacettepe University, Faculty of Medicine, Department of Pediatrics, Division of Metabolism, Ankara, Turkey

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Basri Gülbakan (Presenter)
Hacettepe University

Presenter Bio: Dr. Basri Gülbakan received his PhD degree in Analytical Chemistry under the supervision of Dr.Weihong Tan and Dr.David Powell at University of Florida Deparment of Chemistry and Shands Cancer Center in 2012.
He then moved to ETH Zurich as a Marie Curie Co-fund postdoctoral fellow and worked there between 2012-2015.
His research interests are bioanalytical mass spectrometry methods in particular applyimg mass spectrometric methods for inborn errors of metabolism. He is currently working as an associate professor at Hacettepe University, Institute of Child Health, Division of Metabolism

Relevant Financial Disclosures (within past 24 months)

Grant/Research Support The Scientific and Technological Research Council of Turkey

Conflict mitigation NOT REQUIRED.

Abstract

INTRODUCTION: Inborn errors of metabolism related to biosynthesis and remodelling of phospholipids, sphingolipids is a newly emerging area in inherited metabolic disorders. Phospholipids are synthesized by a de-novo process, known as ‘‘Kennedy pathway’’ and are then dispersed asymmetrically by a remodeling process called ''Lands Cycle''.The MBOAT7, subject of the current study, is located in the Lands lipid remodeling pathway and inserts arachidonic acid to the sn-2 position of lysophosphotidylinositol. While there animal models of the MBOAT7 exist to elucidate its functional role, no study has yet been conducted on the effects of the MBOAT7 gene defect in humans.

OBJECTIVES: The goal this study was to explore the plasma metabolome profile of 12 patients with MBOAT7 gene mutation by mass spectrometry to explore the pathophysiological effects of the MBOAT7 gene defect and identify putative biomarkers.

METHODS: Plasma samples from 12 patients whose MBOAT7 gene defect was confirmed by exome sequencing and of 10 healthy individuals were obtained by following the Hacettepe University Rare Disease Biobank regulations by approval from the Hacettepe University Ethical Review Board. Plasma samples are then extracted and profiled by an Agilent Q-TOF-MS system equipped with 1260 HPLC by using InfinityLab Poroshell 120 RP column in both polarities. The resulting data are then uploaded to XCMS Online and MetaboAnalyst for filtering and data processing. Pooled plasma samples (n=5) were analyzed to calculate the coefficient of variation (CV). Masses whose abundance was not reproducible for all biological replicates, as indicated by a relative standard deviation (RSD) larger than 30 % in QC samples, were discarded.

RESULTS: We have found very significant changes in leukotriene metabolites, bile acids, stereate biosynthesis, and mevalonate pathways. Of note, leukotriene A4 and (5S)-HPETE increase by 4 fold (with p<8.5e-8, 8.4e-11 respectively). Arachidonate decrease by 2.4 and 18R-hydroxy-eicosapentaenoate increase by 4.7 fold. (p< 6.3e-12, 7.5e-7 respectively). The most important common feature of these pathways is their involvement as donors in the lipid remodeling pathway. The identified metabolites mighy give new insights into the pathophysiological changes and molecular mechanisms of the disease.

CONCLUSION: This is the first plasma metabolomics study of the MBOAT7 gene defect in humans. We have shown that patients with MBOAT7 gene defect cannot use arachidonic acid as a donor in lipid modeling and it is metabolized through the conversion of leukotrienes and the lipoxin pathway. We are further investigating the metabolites involved in the identified pathways to explore if they can be considered as valuable biomarkers.