Comprehensive multi-omics analysis of G6PC3 deficiency related congenital neutropenia with inflammatory bowel disease
Guzmán Vega, Francisco J.
Arold, Stefan T.
Ahmed, Syed Osman
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Structural Biology and Engineering
KAUST Grant NumberFCC/1/1976-25
Permanent link to this recordhttp://hdl.handle.net/10754/667720
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AbstractAutosomal recessive mutations in G6PC3 cause isolated and syndromic congenital neutropenia which includes congenital heart disease and atypical inflammatory bowel disease (IBD). In a highly consanguineous pedigree with novel mutations in G6PC3 and MPL, we performed comprehensive multi-omics analyses. Structural analysis of variant G6PC3 and MPL proteins suggests a damaging effect. A distinct molecular cytokine profile (cytokinome) in the affected proband with IBD was detected. Liquid chromatography-mass spectrometry-based proteomics analysis of the G6PC3 deficient plasma samples identified 460 distinct proteins including 75 upregulated and 73 downregulated proteins. Specifically, the transcription factor GATA4 and LST1 were downregulated while platelet factor 4 (PF4) was upregulated. GATA4 and PF4 have been linked to congenital heart disease and IBD respectively, while LST1 may have perturbed a variety of essential cell functions as it is required for normal cell-cell communication. Together, these studies provide potentially novel insights into the pathogenesis of syndromic congenital G6PC3 deficiency.
CitationDasouki, M., Alaiya, A., ElAmin, T., Shinwari, Z., Monies, D., Abouelhoda, M., … Ahmed, S. O. (2021). Comprehensive multi-omics analysis of G6PC3 deficiency related congenital neutropenia with inflammatory bowel disease. iScience, 102214. doi:10.1016/j.isci.2021.102214
SponsorsThe authors wish to thank all the clinicians who provided routine clinical care for these patients and thank the patients and their families who participated in this project. We also acknowledge the Saudi Human Genome Project for infrastructure and informatics support relating to the NGS work. This work was supported by the National Science, Technology, and Innovation Plan program of Saudi Arabia (KACST 13-BIO1978-20). The work by STA and FJGV was supported by the King Abdullah University of Science and Technology (KAUST) through the Award No. FCC/1/1976-25 from the Office of Sponsored Research (OSR).
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