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

Majed Dasouki; Ayodeele Alaiya; Tanziel ElAmin; Zakia Shinwari; Dorota Monies; Mohamed Abouelhoda; Amjad Jabaan; Feras Almourfi; Zuhair Rahbeeni; Fahad Alsohaibani; Fahad Almohareb; Hazzaa Al-Zahrani; Francisco J. Guzmán Vega; Stefan T. Arold; Mahmoud Aljurf; Syed Osman Ahmed

doi:10.1016/j.isci.2021.102214

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

Majed Dasouki, Ayodeele Alaiya, Tanziel ElAmin, Zakia Shinwari, Dorota Monies, Mohamed Abouelhoda, Amjad Jabaan, Feras Almourfi, Zuhair Rahbeeni, Fahad Alsohaibani, Fahad Almohareb, Hazzaa Al-Zahrani, Francisco J. Guzmán Vega, Stefan T. Arold, Mahmoud Aljurf, Syed Osman Ahmed

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Abstract

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.

Original language	English (US)
Pages (from-to)	102214
Journal	iScience
DOIs	https://doi.org/10.1016/j.isci.2021.102214
State	Published - Feb 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-03-01
Acknowledged KAUST grant number(s): FCC/1/1976-25
Acknowledgements: The 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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10.1016/j.isci.2021.102214

https://repository.kaust.edu.sa/bitstream/10754/667720/1/comprehensive_1-s2.0-S2589004221001826-main.pdf

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Dasouki, M., Alaiya, A., ElAmin, T., Shinwari, Z., Monies, D., Abouelhoda, M., Jabaan, A., Almourfi, F., Rahbeeni, Z., Alsohaibani, F., Almohareb, F., Al-Zahrani, H., Guzmán Vega, F. J., Arold, S. T., Aljurf, M., & Ahmed, S. O. (2021). Comprehensive multi-omics analysis of G6PC3 deficiency related congenital neutropenia with inflammatory bowel disease. iScience, 102214. https://doi.org/10.1016/j.isci.2021.102214

@article{b6906b120b5e48beb5c2aebcf1b18009,

title = "Comprehensive multi-omics analysis of G6PC3 deficiency related congenital neutropenia with inflammatory bowel disease",

abstract = "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.",

author = "Majed Dasouki and Ayodeele Alaiya and Tanziel ElAmin and Zakia Shinwari and Dorota Monies and Mohamed Abouelhoda and Amjad Jabaan and Feras Almourfi and Zuhair Rahbeeni and Fahad Alsohaibani and Fahad Almohareb and Hazzaa Al-Zahrani and {Guzm{\'a}n Vega}, {Francisco J.} and Arold, {Stefan T.} and Mahmoud Aljurf and Ahmed, {Syed Osman}",

note = "KAUST Repository Item: Exported on 2021-03-01 Acknowledged KAUST grant number(s): FCC/1/1976-25 Acknowledgements: The 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).",

year = "2021",

month = feb,

doi = "10.1016/j.isci.2021.102214",

language = "English (US)",

pages = "102214",

journal = "iScience",

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Dasouki, M, Alaiya, A, ElAmin, T, Shinwari, Z, Monies, D, Abouelhoda, M, Jabaan, A, Almourfi, F, Rahbeeni, Z, Alsohaibani, F, Almohareb, F, Al-Zahrani, H, Guzmán Vega, FJ, Arold, ST, Aljurf, M & Ahmed, SO 2021, 'Comprehensive multi-omics analysis of G6PC3 deficiency related congenital neutropenia with inflammatory bowel disease', iScience, pp. 102214. https://doi.org/10.1016/j.isci.2021.102214

TY - JOUR

T1 - Comprehensive multi-omics analysis of G6PC3 deficiency related congenital neutropenia with inflammatory bowel disease

AU - Dasouki, Majed

AU - Alaiya, Ayodeele

AU - ElAmin, Tanziel

AU - Shinwari, Zakia

AU - Monies, Dorota

AU - Abouelhoda, Mohamed

AU - Jabaan, Amjad

AU - Almourfi, Feras

AU - Rahbeeni, Zuhair

AU - Alsohaibani, Fahad

AU - Almohareb, Fahad

AU - Al-Zahrani, Hazzaa

AU - Guzmán Vega, Francisco J.

AU - Arold, Stefan T.

AU - Aljurf, Mahmoud

AU - Ahmed, Syed Osman

N1 - KAUST Repository Item: Exported on 2021-03-01 Acknowledged KAUST grant number(s): FCC/1/1976-25 Acknowledgements: The 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).

PY - 2021/2

Y1 - 2021/2

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10754/667720

UR - https://linkinghub.elsevier.com/retrieve/pii/S2589004221001826

U2 - 10.1016/j.isci.2021.102214

DO - 10.1016/j.isci.2021.102214

M3 - Article

C2 - 33748703

SN - 2589-0042

SP - 102214

JO - iScience

JF - iScience

ER -

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

Abstract

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