Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants
Herein, we identified compound heterozygous PROC missense variants in a protein C deficient patient with recurrent thrombotic events, including intestinal necrosis, extrahepatic portal vein obstruction, and lower limb venous thrombosis. The patient's protein C activity and antigen levels were e...
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Elsevier
2025-02-01
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| Series: | American Heart Journal Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666602224001393 |
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| author | Mikio Shiba Shuichiro Higo Yu Morishita Yasuhiro Ichibori Yoshihiro Kin Yasushi Sakata Yoshiharu Higuchi |
| author_facet | Mikio Shiba Shuichiro Higo Yu Morishita Yasuhiro Ichibori Yoshihiro Kin Yasushi Sakata Yoshiharu Higuchi |
| author_sort | Mikio Shiba |
| collection | DOAJ |
| description | Herein, we identified compound heterozygous PROC missense variants in a protein C deficient patient with recurrent thrombotic events, including intestinal necrosis, extrahepatic portal vein obstruction, and lower limb venous thrombosis. The patient's protein C activity and antigen levels were extremely low (<10 % and 5 %, respectively). Exome sequencing analysis revealed two rare missense variants (c.76G>A:p.Val26Met in exon 3 and c.1000G>A:p.Gly334Ser in exon 9), both confirmed to be associated with protein C deficiency and one synonymous variant (c.423G>T:p.Ser141Ser in exon 6) in PROC. PCR amplification of genomic DNA spanning these exons followed by Sanger sequencing analysis revealed that the c.76G>A and the synonymous c.423G>T variants were in the same allele, whereas the c.1000G>A variant was on the opposite allele, indicating compound heterozygosity. Western blot analysis of Huh-7 and HEK293T cells transfected with expression vectors encoding PROC with or without these variants demonstrated that Gly334Ser-PROC expression levels were significantly decreased in culture media collected from HEK293T cells, while the expression levels of protein C with these variants were not significantly altered in cell lysates. This suggests that these variants may affect both protein activity and the secretory process of protein C. |
| format | Article |
| id | doaj-art-6259958cff25432397b9e31b953bf0a7 |
| institution | Kabale University |
| issn | 2666-6022 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | American Heart Journal Plus |
| spelling | doaj-art-6259958cff25432397b9e31b953bf0a72025-02-08T05:01:21ZengElsevierAmerican Heart Journal Plus2666-60222025-02-0150100496Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variantsMikio Shiba0Shuichiro Higo1Yu Morishita2Yasuhiro Ichibori3Yoshihiro Kin4Yasushi Sakata5Yoshiharu Higuchi6Cardiovascular Division, Osaka Police Hospital, Osaka, Japan; Correspondence to: M. Shiba, Cardiovascular Division, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka 543-0035, Japan.Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; Correspondence to: S. Higo, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, JapanCardiovascular Division, Osaka Police Hospital, Osaka, JapanDepartment of Hematology, Daini Osaka Police Hospital, Osaka, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, JapanCardiovascular Division, Osaka Police Hospital, Osaka, JapanHerein, we identified compound heterozygous PROC missense variants in a protein C deficient patient with recurrent thrombotic events, including intestinal necrosis, extrahepatic portal vein obstruction, and lower limb venous thrombosis. The patient's protein C activity and antigen levels were extremely low (<10 % and 5 %, respectively). Exome sequencing analysis revealed two rare missense variants (c.76G>A:p.Val26Met in exon 3 and c.1000G>A:p.Gly334Ser in exon 9), both confirmed to be associated with protein C deficiency and one synonymous variant (c.423G>T:p.Ser141Ser in exon 6) in PROC. PCR amplification of genomic DNA spanning these exons followed by Sanger sequencing analysis revealed that the c.76G>A and the synonymous c.423G>T variants were in the same allele, whereas the c.1000G>A variant was on the opposite allele, indicating compound heterozygosity. Western blot analysis of Huh-7 and HEK293T cells transfected with expression vectors encoding PROC with or without these variants demonstrated that Gly334Ser-PROC expression levels were significantly decreased in culture media collected from HEK293T cells, while the expression levels of protein C with these variants were not significantly altered in cell lysates. This suggests that these variants may affect both protein activity and the secretory process of protein C.http://www.sciencedirect.com/science/article/pii/S2666602224001393ThrombosisInherited protein C deficiencyExome sequencing |
| spellingShingle | Mikio Shiba Shuichiro Higo Yu Morishita Yasuhiro Ichibori Yoshihiro Kin Yasushi Sakata Yoshiharu Higuchi Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants American Heart Journal Plus Thrombosis Inherited protein C deficiency Exome sequencing |
| title | Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants |
| title_full | Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants |
| title_fullStr | Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants |
| title_full_unstemmed | Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants |
| title_short | Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygous PROC missense variants |
| title_sort | protein c deficiency with recurrent systemic thrombosis associated with compound heterozygous proc missense variants |
| topic | Thrombosis Inherited protein C deficiency Exome sequencing |
| url | http://www.sciencedirect.com/science/article/pii/S2666602224001393 |
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