Related Experiment Video
Updated: Oct 14, 2025
Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
Published on: June 9, 2018
[Phenotypic and genotypic analysis of a pedigree affected with hereditary protein C deficiency]
Hongxiang Ding1, Shanshan Li, Lidan Zhu
1Department of Laboratory Medicine, the Second Affiliated Hospital of Wenzhou Medical University, Zhejiang 325088, China. minghua93@126.com.
Insights
Inherited protein C deficiency in a family was linked to a specific PROC gene mutation. This c.1318C>T (p.Arg398Cys) variant likely causes reduced protein C activity and antigen levels.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Inherited protein C deficiency is a rare genetic disorder.
- It increases the risk of venous thromboembolism.
- Understanding the genetic basis is crucial for diagnosis and management.
Purpose of the Study:
- To investigate the genetic cause of protein C deficiency in a multi-generational family.
- To characterize the phenotype and genotype of affected individuals.
- To analyze the functional impact of the identified genetic variant.
Main Methods:
- Pedigree analysis including 7 individuals across 3 generations.
- Assays for plasma protein C activity (PC:A) and antigen (PC:Ag).
- PCR amplification and sequencing of the PROC gene, followed by bioinformatic and protein modeling analysis.
Main Results:
- Four family members showed decreased PC:A and PC:Ag levels.
- Genetic analysis identified a heterozygous c.1318C>T (p.Arg398Cys) missense mutation in the PROC gene in affected individuals.
- Bioinformatic tools predicted the mutation as harmful, and protein modeling revealed altered spatial structure due to disrupted hydrogen bonding.
Conclusions:
- The heterozygous missense mutation c.1318C>T (p.Arg398Cys) in the PROC gene is strongly associated with decreased protein C levels in this pedigree.
- This finding contributes to the understanding of molecular mechanisms underlying inherited protein C deficiency.
Objective:
To analyze the phenotype and genetic variant in a pedigree affected with inherited protein C (PC) deficiency.
Methods:
The proband and her family members (7 individuals from 3 generations) were tested for plasma protein C activity (PC:A), protein C antigen (PC:Ag) content and other coagulation indicators. All of the 9 exons and flanking sequences of the proband's PROC gene were amplified by PCR and sequenced. Suspected variants were verified by reverse sequencing of the proband and her family members. Bioinformatic software was used to analyze the pathogenicity and conservation of the variant site. Swiss-PdbViewer was used to analyze the three-dimensional model and the interaction with the mutant amino acid.
Results:
The PC:A and PC:Ag of the proband, her grandmother, father and elder brother were decreased to 55%, 52%, 48%, 51% and 53%, 55%, 50%, 56%, respectively. Genetic analysis showed that the four individuals have all carried heterozygous c.1318C>T (p.Arg398Cys) missense mutation in exon 9 of the PROC gene. The score of MutationTaster was 0.991, PROVEAN was -3.72, and FATHMM was -2.49, all predicted it to be a harmful mutation. Phylogenetic analysis also showed that Arg398 was weakly conservative among homologous species. Protein model analysis showed that, in the wild type, Arg398 can form a hydrogen bond with Glu341 and Lys395 respectively, when it was mutated to Cys398, the hydrogen bond with Glu341 disappears and an additional hydrogen bond was formed with Lys395, which has changed the spatial structure of the protein.
Conclusion:
The heterozygous missense mutation c.1318C>T (p.Arg398Cys) of the PROC gene probably underlay the decreased PC:A and PC:Ag in this pedigree.
Related Concept Videos
01:35Pedigree Analysis
01:11Genetic Lingo
01:43Incomplete Dominance
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:49Multiple Allele Traits
02:27Background and Environment Affect Phenotype
An example of how genetic background affects phenotype can be seen in horses. The Extension gene in horses is responsible for their coat color. A wild-type gene (EE) produces black pigment in the coat, while a mutant gene (ee) produces red pigment. A...