Phenotypic and genotypic analysis of a pedigree affected with hereditary protein C deficiency due to heterozygous deletional mutation of PROC gene.
10.3760/cma.j.cn511374-20190625-00312
- VernacularTitle:一个杂合缺失变异致遗传性蛋白C缺陷症家系的表型和基因型分析
- Author:
Siqi LIU
1
,
2
;
Fang YU
;
Shasha LUO
;
Xiaolong LI
;
Yanhui JIN
;
Lihong YANG
;
Xingxing ZHOU
;
Haiyue ZHANG
;
Mingshan WANG
Author Information
1. Department of Clinical Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Zhejiang 325000, China. wywms@
2. com.
- Publication Type:Journal Article
- From:
Chinese Journal of Medical Genetics
2020;37(10):1108-1112
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To analyze the phenotype and genetic variants of a pedigree affected with hereditary protein C (PC) deficiency.
METHODS:The protein C activity (PC:A) of the proband and her family members (a four-generation pedigree including 11 individuals) were tested by chromogenic substrate method, and the protein C antigen (PC:Ag) was detected with an enzyme-linked immunosorbent assay(ELISA). The 9 exons and flanking sequences of the protein C (PROC) gene were amplified by PCR and directly sequenced. Suspected mutation was validated by clone sequencing and in other members of the family. MutationTaster and ClustalX-2.1-win was used to analyze the pathogenicity and conservation of the mutation site,respectively. Three-dimentional protein model and amino acids interaction were analyzed with Swiss-PdbViewer software.
RESULTS:The PC: A and PC: Ag of the proband were decreased to 46% (reference range: 70%-130%) and 50% (referencerange:70%-140%), respectively. Her grandmother,aunt, cousin and younger brother also showed declined PC:A and PC:Ag by approximately 50%. Genetic analysis revealed that the above individuals have all carried a deletional mutation c.1212-1212delG (p.Met364TrpfsX15) in exon 9 of the PROC gene which can cause replacement of Methionine at position 364 by Tryptophan and alteration of 15 downstream amino acids, and produce a premature stop codon at position 378. The score of MutationTaster was 1.000, indicating that the variant is pathogenic. Conservative analysis showed that the 15 altered amino acids are located in a conserved region across nine homologous species. Protein model analysis showed that the mutation has disrupted a catalytic domain of protein C thereby affected its function.
CONCLUSION:The heterozygous c.1212-1212delG deletional mutation in exon 9 of the PROC gene, which was unreported previously,probably accounts for the decrease of PC:A and PC:Ag in this pedigree.
