bims-meglyc 2025-04-27 papers

Issue of 2025–04–27
three papers selected by
Silvia Radenkovic, UMC Utrecht

Am J Hum Genet. 2025 Apr 19. pii: S0002-9297(25)00139-9. [Epub ahead of print]

Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.

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

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.

Keywords: MOGS; N-linked glycosylation; UDP-glucose:glycoprotein glucosyltransferase 1; UGGT1; autosomal recessive; congential disorder of glycosylation; microcephaly; monogenic disorder; neurodevelopmental disorder

DOI: https://doi.org/10.1016/j.ajhg.2025.03.018

Obstet Med. 2025 Apr 16. 1753495X251334520

Sivaranjani P, Bhabani Pegu, Murali Subbaiah, Pooja D, Prabhu Manivannan, Gowri Dorairajan.

Congenital thrombocytopenia results from mutations in genes implicated in megakaryocyte differentiation and/or platelet formation and clearance. We report the case of a 25 year old primigravida who presented with severe macro-thrombocytopenia from the age of 12 years. She delivered an alive female baby at 35 weeks of gestation. She was diagnosed to have GNE gene mutation. GNE gene encodes the key enzyme in sialic acid biosynthesis, glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE/MNK). The mutation is responsible for the reduction in sialic acid biosynthesis and consequently leads to severe congenital thrombocytopenia and/or myopathy. Although no sign of myopathy was observed in this patient; it is possible myopathy can be developed later, thus long-term follow-up with neurology is highly advisable. We recommend the genetic counselling and a segregation analysis of this variant in other affected individuals in the family.

Keywords: GNE mutation; Macro-thrombocytopenia

DOI: https://doi.org/10.1177/1753495X251334520

Cell Metab. 2025 Apr 18. pii: S1550-4131(25)00211-6. [Epub ahead of print]

Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.

Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S Shapiro, Mingyang Liu, George M Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J Andrew Wasserstrom, Wolfgang H Dillmann, Benjamin R Thomson, Kenneth C Bedi, Kenneth B Margulies, Samuel E Weinberg, Hossein Ardehali.

Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.

Keywords: HFpEF; O-GlcNAcylation; endothelial cell; hexokinase 1; mitochondria

DOI: https://doi.org/10.1016/j.cmet.2025.04.001