INSERM UMR1163, Imagine Institute, Université de Paris, Paris, France.
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
J Clin Immunol. 2021 Jul;41(5):958-966. doi: 10.1007/s10875-021-00985-w. Epub 2021 Feb 3.
Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein-Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.
磷酸葡糖变位酶 3（PGM3）缺乏症是一种罕见的先天性糖基化紊乱。大多数常染色体隐性低功能突变的 PGM3 编码的磷酸葡糖变位酶 3 患者表现为湿疹、皮肤和肺部感染、血清 IgE 升高，以及神经和骨骼特征。少数 PGM3 缺乏症患者患有更严重的疾病，几乎没有 T 细胞，严重的骨骼发育不良。我们对两个家族进行了靶向下一代测序，以确定具有发育缺陷的严重联合免疫缺陷的潜在遗传病因。我们在此报告了两个新的纯合错义变异（p.Gly359Asp 和 p.Met423Thr），在来自两个无关联家族的三个严重联合免疫缺陷、神经损伤和骨骼发育不良的患者中发现了 PGM3。这两种变异在两个家族中均与疾病共分离。通过计算机分析预测它们具有有害性。在携带 p.Met423Thr 变异的家族中，原发性成纤维细胞和 Epstein-Barr 病毒永生化 B 细胞中的 PGM3 酶活性被发现严重受损。我们的研究结果支持这两种新变异在严重 PGM3 缺乏症中的致病性。
