Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study

Biguzzi, Eugenia; Razzari, Cristina; Lane, David A.; Castaman, Giancarlo; Cappellari, Antonio; Bucciarelli, Paolo; Fontana, Gessica; Margaglione, Maurizio; D’Andrea, Giovanna; Simmonds, Rachel E.; Rezende, Suely Meireles; Preston, Roger J. S.; Prisco, Domenico; Faioni, Elena M.

doi:10.1002/humu.20136

Cited by 50 publications

(47 citation statements)

References 49 publications

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“…This mutation has been reported previously [19] and results in the substitution of Glu 67 to Ala. Glu 67 is required for vitamin K-dependent proteins to bind Ca 2+ and bind to phospholipid membranes [20]. Glu 67 also appears to be important for protein S secretion from the liver into blood [19]. A second mutation was identified in the 5' flanking sequence of the PROS1 gene ( Figure 1B), and represented a heterozygous CG nucleotide substitution at a position 190 bp upstream of the translational start site ( Figure 1C).…”

Section: Resultssupporting

confidence: 59%

“…An exon mutation (PROS1 c.200 A>C) was identified in exon 2 of the patient's PROS1 gene ( Figure 1B). This mutation has been reported previously [19] and results in the substitution of Glu 67 to Ala. Glu 67 is required for vitamin K-dependent proteins to bind Ca 2+ and bind to phospholipid membranes [20]. Glu 67 also appears to be important for protein S secretion from the liver into blood [19].…”

Section: Resultsmentioning

confidence: 92%

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Identification of two novel mutations associated with combined protein C and protein S deficiency

Smith¹,

Carter²,

Smith³

et al. 2017

Vascul Dis Ther

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We have studied a 60 year old male of Chinese descent who presented with combined deficiency of the anticoagulant proteins C and S. Molecular genetic analysis of the patient's PROC gene revealed a novel heterozygous mutation that resulted in a V221G mutation. Two mutations were identified in the patient's PROS1 gene:(1) an E67E mutation that has been reported previously and is associated with severe protein S deficiency, and (2) a novel mutation in the 5' flanking sequence that changes a putative binding site for the transcription factor Sp 1. Together, these mutations are consistent with the combined protein C and S deficiency symptoms presented by the patient.

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Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 92%

Identification of two novel mutations associated with combined protein C and protein S deficiency

Smith¹,

Carter²,

Smith³

et al. 2017

Vascul Dis Ther

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“…1) and designated it as protein S Sapporo 1. Protein S Sapporo 1 is a novel mutation of the PROS1 gene that is not described in the 2000 ISTH database of PS mutations [16], the HGMD PROS1 database, or recent reports [12][13][14][15]. The proband, as well as his mother and elder brother, were phenotypically diagnosed with type I deficiency (Table I).…”

Section: Discussionmentioning

confidence: 99%

“…All amplified segments were sequenced in both directions. Exon sequence numbering of the PROS1 gene was done according to the method of Schmidel et al [5], as adopted by Biguzzi et al [14] [PROS1 cDNA NCBI GenBank accession number NM_000313.1 (þ1 corresponds to the A of the ATG translation initiation codon)]. Amino acid residues of PS were numbered according to the method presented in the 2000 ISTH protein S database [16].…”

Section: Dna Sequence Analysismentioning

confidence: 99%

“…Type III deficiency is characterized by normal total PS antigen levels, but low free PS antigen levels and low PS activity. According to the Human Gene Mutation Database (HGMD) PROS1 database (URL: http:// archive.uwcm.ac.uk/uwcm/mg/search/120721.html) and recent reports [12][13][14][15], 189 mutations have been identified thus far in the PROS1 gene, most within families with type I and/or type III PS deficiency. Although this classification has been widely used, a newly proposed classification system suggests that PS deficiency can be categorized as quantitative deficiency (old type I and type III deficiency) and qualitative deficiency (type II deficiency), as reported by the 2000 The International Society on Thrombosis and Hemostasis (ISTH) [16].…”

Section: Introductionmentioning

confidence: 99%

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One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosis

et al. 2006

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We investigated the molecular basis of type I protein S (PS) deficiency in two unrelated Japanese families, in which both probands developed pulmonary embolism associated with deep vein thrombosis. Nucleotide sequencing of amplified DNA revealed distinct point mutations in the PROS1 gene of the probands, which were designated protein S Sapporo 1 and protein S Sapporo 2. Additional mutations in the PROS1 gene were excluded by DNA sequencing of all exons and intron/exon boundaries. In the 25-year-old Japanese male patient who carried protein S Sapporo 1, we identified a heterozygous A-to-T change in the invariant ag dinucleotide of the acceptor splice site of intron f of the PROS1 gene. This mutation is a novel splice site mutation that impairs normal mRNA splicing, leading to exon 7 skipping, which was confirmed by platelet mRNA analysis. Translation of this mutant transcript would result in a truncated protein that lacks the entire epidermal growth factor-like domain 3 of the PS molecule. In a 31-year-old Japanese male and his younger brother who each carried protein S Sapporo 2, we detected a previously described heterozygous T-to-C transition at nucleotide position 1147 in exon 10 of the PROS1 gene, which predicts an amino acid substitution of tryptophan by arginine at residue 342 in the laminin G1 domain of the PS molecule. Both mutations would cause misfolding of the PS protein, resulting in the impairment of secretion, which is consistent with the type I PS deficiency phenotype. Am. J. Hematol. 81:787-797, 2006. V V C 2006 Wiley-Liss, Inc.

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Molecular basis of protein S deficiency in China

et al. 2013

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Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the downregulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation. Am. J.

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Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study

Cited by 50 publications

References 49 publications

Identification of two novel mutations associated with combined protein C and protein S deficiency

Identification of two novel mutations associated with combined protein C and protein S deficiency

One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosis

Molecular basis of protein S deficiency in China

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