Compound heterozygous protein C deficiency in a family with venous thrombosis: Identification and in vitro study of p.Asp297His and p.Val420Leu mutations

Liu, Hui; Wang, Huafang; Tang, Liang; Yang, Yan; Wang, Qingyun; Zeng, Wenbin; Wu, Yingying; Cheng, Zhengwang; Hu, Bei; Guo, Tao; Hu, Yu

doi:10.1016/j.gene.2015.03.002

Cited by 13 publications

(10 citation statements)

References 23 publications

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“…The onset age and mode of the late‐onset patients with double mutations were varied. Late‐onset patients with the double mutations of PROC are rarely reported in Caucasians but are increasing in number in Asian countries (Table ). This discrepancy may be due to the high allelic frequency of FV Leiden and FII variant in Caucasians, which hampers the detection of rare double PROC mutations in adult patients.…”

Section: Discussionmentioning

confidence: 99%

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene

Inoue

Terachi

Uchiumi

et al. 2017

Pediatr Blood Cancer

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Section: Discussionmentioning

confidence: 99%

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene

Inoue

Terachi

Uchiumi

et al. 2017

Pediatr Blood Cancer

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“…COS7 cells were used to present the receptor’s subcellular localization because of its prominent membrane structure that makes it easy to distinguish the specific location of V2R proteins. WT-V2R and I324M-V2R were co-stained with protein disulfide isomerase (PDI) and Golgi marker (GM130), which are used as the markers of endoplasmic reticulum (ER) and Golgi apparatus, respectively 25 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus

Wang

Guo

Fang

et al. 2021

Sci Rep

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X-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly “rescue” I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI.

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“…Moreover, qualitative PCD was previously observed in carriers of other mutations at position 385, 420, and 423. [23][24][25] In the type I mutation category, p. Asn371Asp was considered to be "likely pathogenic," despite its high frequency (gnomAD: 0.03%) and low in silico prediction scores, for two main reasons. First, Asn 371 is one of the four N-linked glycosylation sites of PC and another mutation at It has been previously reported in case-control studies of VTE that two polymorphisms in the promoter region of PROC (-228C > T and -215G > A) had a significant influence on PC level and risk of VTE.…”

Section: Genotype and Pc Phenotypementioning

confidence: 99%

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

et al. 2020

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Inherited protein C (PC) deficiency caused by mutations in the PROC gene is a well-known risk factor for venous thromboembolism. Few studies have investigated the relationship between PROC genotype and plasma or clinical phenotypes. We addressed this issue in a large retrospective cohort of 1,115 heterozygous carriers of 226 PROC pathogenic or likely pathogenic mutations. Mutations were classified in three categories according to their observed or presumed association with type I, type IIa, or type IIb PC deficiency. The study population comprised 876 carriers of type I category mutations, 55 carriers of type IIa category mutations, and 184 carriers of type IIb category mutations. PC anticoagulant activity significantly influenced risk of first venous thrombosis (p trend < 10−4). No influence of mutation category on risk of whole or unprovoked thrombotic events was observed. Both PC anticoagulant activity and genotype significantly influenced risk of venous thrombosis. Effect of detrimental mutations on plasma phenotype was ambiguous in several carriers, whatever the mutation category. Altogether, our findings confirm that diagnosing PC inherited deficiency based on plasma measurement may be difficult but show that diagnosis can be improved by PROC genotyping.

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Compound heterozygous protein C deficiency in a family with venous thrombosis: Identification and in vitro study of p.Asp297His and p.Val420Leu mutations

Cited by 13 publications

References 23 publications

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene

Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

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