Characterization of an IDS pathogenic variant in a family with mucopolysaccharidosis type Ⅱ
10.3760/cma.j.cn311282-20220112-00016
- VernacularTitle:一个黏多糖贮积症Ⅱ型家系的IDS基因致病变异特征分析
- Author:
Hanfei YU
1
;
Qian QIN
;
Jie WU
;
Xueyuan JIA
;
Wei JI
;
Xuelong ZHANG
;
Lidan XU
;
Kexian DONG
;
Rongwei GUAN
;
Hao WANG
;
Wenjing SUN
Author Information
1. 中国遗传资源保护与疾病防控教育部重点实验室（哈尔滨医科大学），哈尔滨医科大学医学遗传学研究室 150081
- Keywords:
Mucopolysaccharidosis type Ⅱ;
Iduronate-2-sulfatase gene;
Whole exome sequencing;
c. 323A>C: p.Y108S variation
- From:
Chinese Journal of Endocrinology and Metabolism
2023;39(4):345-352
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To identify the genetic variation in a mucopolysaccharidosis type Ⅱ(MPS Ⅱ)family, and conduct a functional study of iduronate-2-sulfatase(IDS): c.323A>C.Methods:A five-generation MPS Ⅱ family of 83 individuals including 4 patients from northern China was collected. Urine mucopolysaccharide and Alder-Reilly body were tested to assist the clinical diagnosis of MPS Ⅱ. IDS enzyme activity was detected on core family members. By the whole exome sequencing of a MPS Ⅱ patient in this family and bioinformatics analysis, the variant was screened and further identified by PCR-Sanger sequencing. Finally, to validate the function of the variant in vitro, the wild-type IDS overexpression plasmid(pCMV-hIDS-WT)and the IDS overexpression plasmid carrying the mutation site(pCMV-hIDS-c.323A>C)were transfected into COS-7 cells and the IDS activity was detected. Results:The proband(Ⅳ3)and Ⅳ4 were diagnosed as MPS Ⅱ by urine mucopolysaccharide, Alder-Reilly body, and IDS enzyme activity tests. Ⅳ3, Ⅳ4, Ⅲ19, and Ⅲ32 were determined to carry IDS: c.323A>C missense variant through the whole-exome sequencing, and diagnosed as MPS Ⅱ. Meanwhile, Ⅱ2, Ⅱ4, Ⅱ8, Ⅱ12, Ⅱ14, Ⅲ5, Ⅲ7, Ⅳ14 in the MPS Ⅱ family carried IDS: c.323A>C missense variant, and were excluded as MPS Ⅱ. The in vitro experiment in COS-7 cells showed that the missense mutation led to a significant decrease in IDS enzyme activity. Conclusion:The variant IDS: c.323A>C: p.Y108S significantly decreases the activity of IDS enzyme in vivo and in vitro, and it is identified as a pathogenic variant for MPS Ⅱ.
