PGM1-CDG的发病机理和治疗过程中的代谢图。,American Journal of Human Genetics

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PGM1-CDG的发病机理和治疗过程中的代谢图。
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-04-11 , DOI: 10.1016/j.ajhg.2019.03.003
Silvia Radenkovic ₁ , Matthew J Bird ₂ , Tim L Emmerzaal ₃ , Sunnie Y Wong ₄ , Catarina Felgueira ₅ , Kyle M Stiers ₆ , Leila Sabbagh ₄ , Nastassja Himmelreich ₇ , Gernot Poschet ₈ , Petra Windmolders ₅ , Jan Verheijen ₉ , Peter Witters ₁₀ , Ruqaiah Altassan ₁₁ , Tomas Honzik ₁₂ , Tuba F Eminoglu ₁₃ , Phillip M James ₁₄ , Andrew C Edmondson ₁₅ , Jozef Hertecant ₁₆ , Tamas Kozicz ₁₇ , Christian Thiel ₇ , Pieter Vermeersch ₁₈ , David Cassiman ₁₉ , Lesa Beamer ₆ , Eva Morava ₂₀ , Bart Ghesquière ₂₁

Affiliation

Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Clinical Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium.
Department of Anatomy, Radboud University Medical Centre, Donders Institute for Brain Cognition and Behaviour, 6535 HR Nijmegen, the Netherlands.
Hayward Genetics Center, Tulane University School of Medicine, New Orleans, LA 70112, LA, USA.
Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Biochemistry Department, University of Missouri, Columbia, MO 65211, USA.
Center for Child and Adolescent Medicine, Department I, University of Heidelberg, 69120 Heidelberg, Germany.
Centre for Organismal Studies, University of Heidelberg, 69120 Heidelberg, Germany.
Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium.
Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium; Medical Genetics Department, Montréal Children's Hospital, McGill University, Montreal, QC H4A3J1, Canada.
Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague, Czech Republic.
Department of Pediatric Metabolism and Nutrition, Ankara University School of Medicine, 06560 Ankara, Turkey.
Phoenix Children's Medical Group, Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
Division of Human Genetics, Department of Pediatrics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Pediatrics, United Arab Emirates University, Al Ain, United Arab Emirates.
Department of Anatomy, Radboud University Medical Centre, Donders Institute for Brain Cognition and Behaviour, 6535 HR Nijmegen, the Netherlands; Hayward Genetics Center, Tulane University School of Medicine, New Orleans, LA 70112, LA, USA; Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Clinical Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium; Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium.
Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium.
Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.

磷酸葡萄糖突变酶1（PGM1）编码可相互转换葡萄糖6-P和葡萄糖-1-P的代谢酶。PGM1中的突变会导致糖原代谢和糖基化受损，后者表现为先天性糖基化疾病（CDG）。这种独特的代谢缺陷会导致内质网（ER）和高尔基体（GA）中的N-聚糖合成异常。基于聚糖链中半乳糖基化的减少，已将半乳糖施用于患有PGM1-CDG的个体，并显示出可显着逆转大多数与疾病相关的实验室异常。但是，该疾病和治疗机制仍然难以捉摸。在这里，我们证实在受PGM1-CDG影响的个体中补充半乳糖的临床益处，并获得了糖基化功能和生化调节的重要见解。我们在这里报告说，通过使用基于示踪剂的代谢组学，我们发现半乳糖治疗PGM1-CDG成纤维细胞在代谢上重新关联了其糖代谢，因此补充了半乳糖-1-P的消耗水平以及UDP-葡萄糖和UDP-半乳糖，分别是ER和GA连接的糖基化所需的核苷酸糖。为此，我们进一步表明，UDP-半乳糖中的半乳糖被掺入成熟的从头聚糖中。我们的研究结果还暗示了单糖治疗其他几种CDG的潜力。分别是ER和GA连接的糖基化所需的核苷酸糖。为此，我们进一步表明，UDP-半乳糖中的半乳糖被掺入成熟的从头聚糖中。我们的研究结果还暗示了单糖治疗其他几种CDG的潜力。分别是ER和GA连接的糖基化所需的核苷酸糖。为此，我们进一步表明，UDP-半乳糖中的半乳糖被掺入成熟的从头聚糖中。我们的研究结果还暗示了单糖治疗其他几种CDG的潜力。

"点击查看英文标题和摘要"

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.

更新日期：2019-05-16

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