Dardas Zain, Harrold Laura, Calame Daniel G, Salter Claire G, Kikuma Takashi, Guay Kevin P, Ng Bobby G, Sano Kanae, Saad Ahmad K, Du Haowei, Sangermano Riccardo, Patankar Sohil G, Jhangiani Shalini N, Gürsoy Semra, Abdel-Hamid Mohamed S, Ahmed Mahmoud K H, Maroofian Reza, Kaiyrzhanov Rauan, Salayev Kamran, Jones Wendy D, Pérez Caballero Ana, McGavin Lucy, Spiller Michael, Durkie Miranda, Wood Nick, O'Grady Lauren, Goldenberg Paula, Neumeyer Ann M, Begtrup Amber, Abdel-Ghafar Sherif F, Zaki Maha S, Van Esch Hilde, Posey Jennifer E, Wenger Olivia K, Scott Ethan M, Bujakowska Kinga M, Gibbs Richard A, Pehlivan Davut, Marafi Dana, Leslie Joseph S, Ubeyratna Nishanka, Day Jacob, Owens Martina, Settle Jessica, Balkhy Soher, Tamim Abdullah, Alabdi Lama, Alkuraya Fowzan S, Takeda Yoichi, Freeze Hudson H, Hebert Daniel N, Lupski James R, Crosby Andrew H, Baple Emma L
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
Am J Hum Genet. 2025 May 1;112(5):1139-1157. doi: 10.1016/j.ajhg.2025.03.018. Epub 2025 Apr 22.
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.
先天性糖基化障碍（CDG）是一组由糖蛋白和糖脂聚糖组装及重塑缺陷引起的代谢性疾病，种类繁多且异质性强，这是一个具有广泛生物学作用的基本分子过程。在此，我们描述了来自十个不同种族背景的不相关家庭的15名个体中的双等位基因UGGT1变异，这是一种严重程度各异的独特CDG的病因。UGGT1 - CDG的主要临床特征包括发育迟缓、智力残疾、癫痫发作、特征性面部特征以及大多数患者（11名有测量数据的患者中有9名）出现小头畸形。受影响更严重的个体表现出先天性心脏畸形、包括脊柱侧弯在内的各种骨骼异常，以及肝脏和肾脏受累，包括类似常染色体隐性多囊肾病的多囊肾。临床研究确定了基因型与表型的相关性，表明双等位基因UGGT1功能丧失变异与疾病严重程度增加相关，包括婴儿期死亡。UGGT1编码UDP - 葡萄糖：糖蛋白葡糖基转移酶1，这是一种对维持N - 连接糖基化质量控制至关重要的酶。分子研究表明，致病性UGGT1变异会损害UGGT1的糖基化和催化活性、破坏mRNA剪接或抑制内质网（ER）滞留。总体而言，我们的数据提供了UGGT1 - CDG全面的遗传、临床和分子特征，拓宽了N - 连接糖基化障碍的范围。
