Comprehensive multi-omics analysis of G6PC3 deficiency-related congenital neutropenia with inflammatory bowel disease

Autosomal 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...

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Bibliographic Details
Published in:	iScience Vol. 24; no. 3; p. 102214
Main Authors:	Dasouki, Majed, Alaiya, Ayodeele, ElAmin, Tanziel, Shinwari, Zakia, Monies, Dorota, Abouelhoda, Mohamed, Jabaan, Amjad, Almourfi, Feras, Rahbeeni, Zuhair, Alsohaibani, Fahad, Almohareb, Fahad, Al-Zahrani, Hazzaa, Guzmán Vega, Francisco J., Arold, Stefan T., Aljurf, Mahmoud, Ahmed, Syed Osman
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 19-03-2021 Elsevier
Subjects:	Genomics Pathophysiology Proteomics Systems Biology Pathophysiology Systems Biology Genomics Proteomics
Online Access:	Get full text
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Summary:	Autosomal 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. [Display omitted] •Multi-omics approaches identify unique signatures•Whole-exome sequencing reveals distinct cytokine profiles•Expression of GATA4, PF4, and LST1 is dysregulated Pathophysiology ; Systems Biology ; Genomics ; Proteomics ;
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead contact
ISSN:	2589-0042 2589-0042
DOI:	10.1016/j.isci.2021.102214