Genomic, Proteomic, and Phenotypic Spectrum of Novel O-Sialoglycoprotein Endopeptidase Variant in Four Affected Individuals With Galloway-Mowat Syndrome

Malak Ali Alghamdi; Hicham Benabdelkamel; Afshan Masood; Narjes Saheb Sharif-Askari; Mahmood Y Hachim; Hamad Alsheikh; Muddathir H Hamad; Mustafa A Salih; Fahad A Bashiri; Khalid Alhasan; Tarek Kashour; Pilar Guatibonza Moreno; Sabine Schröder; Vasiliki Karageorgou; Aida M Bertoli-Avella; Hisham Alkhalidi; Dima Z Jamjoom; Ibrahim A Alorainy; Assim A Alfadda; Rabih Halwani

doi:10.3389/fgene.2022.806190

Genomic, Proteomic, and Phenotypic Spectrum of Novel O-Sialoglycoprotein Endopeptidase Variant in Four Affected Individuals With Galloway-Mowat Syndrome

Front Genet. 2022 Jun 23:13:806190. doi: 10.3389/fgene.2022.806190. eCollection 2022.

Authors

Malak Ali Alghamdi^{1

2}, Hicham Benabdelkamel³, Afshan Masood³, Narjes Saheb Sharif-Askari⁴, Mahmood Y Hachim⁵, Hamad Alsheikh⁶, Muddathir H Hamad⁶, Mustafa A Salih¹, Fahad A Bashiri^{1

6}, Khalid Alhasan^{1

7

8}, Tarek Kashour⁹, Pilar Guatibonza Moreno¹⁰, Sabine Schröder¹⁰, Vasiliki Karageorgou¹⁰, Aida M Bertoli-Avella¹⁰, Hisham Alkhalidi¹¹, Dima Z Jamjoom¹², Ibrahim A Alorainy¹², Assim A Alfadda^{3

13

14}, Rabih Halwani¹⁵

Affiliations

¹ Pediatric Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
² Medical Genetics Division, Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia.
³ Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁴ Sharjah Institute for Medical Research, University of Sharjah, Dubai, United Arab Emirates.
⁵ College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
⁶ Neurology Division, Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia.
⁷ Nephology Division, Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia.
⁸ Pediatric Kidney Transplant Division,Organ Transplant Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
⁹ Cardiology Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹⁰ CENTOGENE GmbH, Rostock, Germany.
¹¹ Pathology Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹² Radiology and Medical Imaging Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹³ Department of Medicine, College of Medicine and King Saud Medical City, King Saud University, Riyadh, Saudi Arabia.
¹⁴ Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹⁵ Department of Clinical Sciences, College of Medicine, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates.

Abstract

Galloway-Mowat syndrome is a rare autosomal recessive disease characterized by a unique combination of renal and neurological manifestations, including early-onset steroid-resistant nephrotic syndrome, microcephaly, psychomotor delay, and gyral abnormalities of the brain. Most patients die during early childhood. Here, we identified a novel homozygous O-sialoglycoprotein endopeptidase (OSGEP) variant, NM_017807.3:c.973C>G (p.Arg325Gly), in four affected individuals in an extended consanguineous family from Saudi Arabia. We have described the detailed clinical characterization, brain imaging results, and muscle biopsy findings. The described phenotype varied from embryonic lethality to early pregnancy loss or death at the age of 9. Renal disease is often the cause of death. Protein modeling of this OSGEP variant confirmed its pathogenicity. In addition, proteomic analysis of the affected patients proposed a link between the KEOPS complex function and human pathology and suggested potential pathogenic mechanisms.

Keywords: GAMOS; Galloway-Mowat syndrome; KEOPS complex; proteomic; steroid-resistant nephrotic syndrome.

Copyright © 2022 Ali Alghamdi, Benabdelkamel, Masood, Saheb Sharif-Askari, Hachim, Alsheikh, Hamad, Salih, Bashiri, Alhasan, Kashour, Guatibonza Moreno, Schröder, Karageorgou, Bertoli-Avella, Alkhalidi, Jamjoom, Alorainy, Alfadda and Halwani.