SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals
SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals
复制标题
DOI：
10.1002/humu.23731
复制
发表时间：
2019-07-01
期刊：
影响因子：
3.9
通讯作者：
Freeze, Hudson H.
中科院分区：
文献类型：
--
作者：
Ng, Bobby G.;Sosicka, Paulina;Freeze, Hudson H.
X-连锁基因SLC 35 A2中的致病性新生变异体编码适当蛋白质和脂质糖基化所需的主要高尔基体定位的UDP-半乳糖转运蛋白，导致一种罕见类型的先天性糖基化疾病，称为SLC 35 A2-先天性糖基化疾病（CDG;以前称为CDG-IIm）。迄今为止，文献中已描述了来自32个无关个体的29种独特的从头变异。大多数受影响的个体的主要特征是不同程度的神经损伤，伴有或不伴有骨骼异常。令人惊讶的是，大多数受影响的个体在血清转铁蛋白N-糖基化方面没有显示出异常，这是大多数类型的CDG的常见生物标志物。在这里，我们展示了30个个体的特征数据，并增加了26个新的变体，这是涉及SLC 35 A2-CDG的最大的研究。这些人中的绝大多数具有正常的转铁蛋白糖基化。此外，扩大了这种罕见疾病的分子和临床谱，我们开发了一种稳健可靠的生化测定法来评估原代成纤维细胞中SLC 35 A2依赖性UDP-半乳糖转运活性。最后，我们表明，运输活动是直接相关的比例野生型突变等位基因在成纤维细胞从受影响的个人。
Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.