Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation

Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic conditions caused by defects in glycoprotein and glycolipid glycan assembly and remodeling, a fundamental molecular process with wide-ranging biological roles. Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from ten unrelated families of various ethnic backgrounds as a cause of a distinctive CDG of variable severity. The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including scoliosis, and hepatic and renal involvement, including polycystic kidneys mimicking autosomal recessive polycystic kidney disease. Clinical studies defined genotype-phenotype correlations, showing bi-allelic UGGT1 loss-of-function variants associated with increased disease severity, including death in infancy. UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme critical for maintaining quality control of N-linked glycosylation. Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention. Collectively, our data provide a comprehensive genetic, clinical, and molecular characterization of UGGT1-CDG, broadening the spectrum of N-linked glycosylation disorders.

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Publication Details

Journal
The American Journal of Human Genetics
Published
2025-04-22
DOI
https://doi.org/10.1016/j.ajhg.2025.03.018
Citations
4
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
3.22

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article

Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation

Sherif F. Abdel‐Ghafar, Michael W. Spiller, Ann M. Neumeyer, Kinga M. Bujakowska et al.
4 citations
The American Journal of Human Genetics
Glycosylation and Glycoproteins Research
3.22
article

Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation

Sherif F. Abdel‐Ghafar, Michael W. Spiller, Ann M. Neumeyer, Kinga M. Bujakowska, Riccardo Sangermano, Jennifer E. Posey, Lauren O’Grady, Hudson H. Freeze, Maha Saad Zaki, Zain Dardas, Bobby G. Ng, Davut Pehli̇van, Kamran Salayev, Kanae Sano, Dana Marafi, Nishanka Ubeyratna, Daniel G. Calame, Ethan M. Scott, Daniel N. Hebert, Andrew H. Crosby, Amber Begtrup, Yoichi Takeda, Armando Caballero, Soher Balkhy, Lama AlAbdi, Richard A. Gibbs, Mahmoud K.H. Ahmed, Paula Goldenberg, Nicholas William Wood, Takashi Kikuma, Hilde Van Esch, Miranda Durkie, Shalini N. Jhangiani, Martina Owens, Joseph S. Leslie, Claire Salter, Mohamed S. Abdel‐Hamid, Laura Harrold, Semra Gürsoy, Fowzan Sami Alkuraya, Haowei Du, Amr S. Saad, Kevin P. Guay, Abdullah Tamim, Jacob Day, Emma L. Baple, Olivia Wenger, Lucy McGavin, Sohil G Patankar, Rauan Kaiyrzhanov, Wendy D Jones, Reza Maroofian, James R. Lupski, Jessica Settle
article en
4 citations

Abstract

Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic conditions caused by defects in glycoprotein and glycolipid glycan assembly and remodeling, a fundamental molecular process with wide-ranging biological roles. Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from ten unrelated families of various ethnic backgrounds as a cause of a distinctive CDG of variable severity. The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including scoliosis, and hepatic and renal involvement, including polycystic kidneys mimicking autosomal recessive polycystic kidney disease. Clinical studies defined genotype-phenotype correlations, showing bi-allelic UGGT1 loss-of-function variants associated with increased disease severity, including death in infancy. UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme critical for maintaining quality control of N-linked glycosylation. Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention. Collectively, our data provide a comprehensive genetic, clinical, and molecular characterization of UGGT1-CDG, broadening the spectrum of N-linked glycosylation disorders.

The American Journal of Human GeneticsVol. 112(5)
Massachusetts Eye and Ear Infirmary (US), Boston Children's Hospital (US), Clinic for Special Children (US), Ritsumeikan University (JP), Amherst College (US), Baylor College of Medicine (US), Sanford Burnham Prebys Medical Discovery Institute (US), Dokuz Eylül University (TR), University of Exeter (GB), University of Massachusetts Amherst (US), Discovery Institute (US), Royal Devon & Exeter NHS Foundation Trust (GB), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), King Faisal Specialist Hospital & Research Centre (SA), Princess Anne Hospital (GB), Kuwait University (KW), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Eaton (United States) (US), Sheffield Children's NHS Foundation Trust (GB), National Research Centre (EG), New Leaf Center (US), Texas Children's Hospital (US), National Hospital for Neurology and Neurosurgery (GB), Baylor Genetics (US), Bradford Teaching Hospitals NHS Foundation Trust (GB), University Hospitals Plymouth NHS Trust (GB), University College London (GB), Center for Autism and Related Disorders (US), KU Leuven (BE)
Research to Prevent Blindness, Muscular Dystrophy Association, Johns Hopkins University, Wellcome Trust, National Institute for Health and Care Research, Science and Technology Development Fund, National Institutes of Health, Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Zero hunger
Openalex Percentile: Top 9%
Glycosylation and Glycoproteins Research
3.22
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