Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
Pediatr Allergy Immunol. 2021 Apr;32(3):566-575. doi: 10.1111/pai.13398. Epub 2020 Nov 6.
Phosphoglucomutase-3 (PGM3) deficiency is a congenital disorder of glycosylation (CDG) with hyperimmunoglobulin IgE, atopy, and a variable immunological phenotype; most reported patients display dysmorphic features. The aim of the study was to characterize the genotype and phenotype of individuals with newly identified compound heterozygous variants in the phosphate-binding domain of PGM3 in order to better understand phenotypic differences between these patients and published cases.
We analyzed PGM3 protein expression, PGM3 enzymatic activity, the presence of other gene variants within the N-glycosylation pathway, and the clinical and immunological manifestations of two affected siblings.
Patients belonged to a non-consanguineous family, presenting with atopic dermatitis, elevated levels of IgE, and CD4 lymphopenia (a more severe phenotype was observed in Patient 2), but lacked dysmorphic features or neurocognitive impairment. Compound heterozygous PGM3 variants were identified, located in the phosphate-binding domain of the enzyme. PGM3 expression was comparable to healthy donors, but L-PHA binding in naïve-CD4+ cells was decreased. Examination of exome sequence identified the presence of one additional candidate variant of unknown significance (VUS) in the N-glycosylation pathway in Patient 2: a variant predicted to have moderate-to-high impact in ALG12.
Our analysis revealed that L-PHA binding is reduced in naïve-CD4+ cells, which is consistent with decreased residual PGM3 enzymatic activity. Other gene variants in the N-glycosylation pathway may modify patient phenotypes in PGM3 deficiency. This study expands the clinical criteria for when PGM3 deficiency should be considered among individuals with hyper-IgE.
磷酸葡萄糖变位酶 3（PGM3）缺乏症是一种伴有高免疫球蛋白 E、特应性和可变免疫表型的先天性糖基化障碍（CDG）；大多数报道的患者表现出畸形特征。本研究的目的是描述新鉴定的 PGM3 磷酸盐结合域中复合杂合变异个体的基因型和表型，以便更好地理解这些患者与已发表病例之间的表型差异。
我们分析了 PGM3 蛋白表达、PGM3 酶活性、N-糖基化途径中其他基因变异的存在以及两名受影响的同胞的临床和免疫学表现。
患者来自非近亲家庭，表现为特应性皮炎、IgE 水平升高和 CD4 淋巴细胞减少（在患者 2 中观察到更严重的表型），但缺乏畸形特征或神经认知障碍。鉴定出位于酶磷酸结合域的复合杂合 PGM3 变异。PGM3 表达与健康供体相当，但幼稚 CD4+细胞中 L-PHA 结合减少。外显子组序列检查发现患者 2 中 N-糖基化途径存在另一个未知意义的候选变异（VUS）：一种预测在 ALG12 中具有中至高影响的变异。
我们的分析表明，幼稚 CD4+细胞中的 L-PHA 结合减少，这与残余 PGM3 酶活性降低一致。N-糖基化途径中的其他基因变异可能会改变 PGM3 缺乏症患者的表型。这项研究扩展了在高免疫球蛋白 E 个体中应考虑 PGM3 缺乏症的临床标准。
