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[PMID]: | 28088608 |
[Au] Autor: | Taniguchi F; Morishita E; Sekiya A; Nomoto H; Katsu S; Kaneko S; Asakura H; Ohtake S |
[Ad] Endereço: | Department of Clinical Laboratory Science, Kanazawa University, Graduate School of Medical Science, 5-11-80 Kodatsuno Kanazawa, Ishikawa 920-0942, Japan; Department of Central Clinical Laboratory, Kanazawa Medical University Hospital, 1-1 Daigaku Uchinada Kahoku, Ishikawa 920-0293, Japan. |
[Ti] Título: | Gene analysis of six cases of congenital protein S deficiency and functional analysis of protein S mutations (A139V, C449F, R451Q, C475F, A525V and D599TfsTer13). |
[So] Source: | Thromb Res;151:8-16, 2017 Mar. | [Is] ISSN: | 1879-2472 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Congenital deficiency of protein S (PS), an anticoagulant factor, leads to venous thrombosis, with onset predominantly beginning in adolescence. In the present study, gene analysis of six unrelated Japanese families diagnosed with congenital PS deficiency identified five missense mutations in the PROS1 gene - c.757C>T (Ala139Val; A139V), c.1346 G>T (Cys449Phe; C449F), c.1352G>A (Arg451Gln; R451Q), c.1424G>T (Cys475Phe; C475F) and c.1574C>T (Ala525Val; A525V) - and one frameshift mutation, c.2135delA (Asp599ThrfsTer13; D599TfsTer13). C449F, R451Q, A525V and D599TfsTer13 are novel mutations. Results from ELISA to measure PS antigen levels in culture supernatant showed that the A139V variant was similar to wild-type, but other variants showed reductions when compared with wild-type. Results from pulse-chase analysis confirmed that the A139V variant exhibited secretion equivalent to wild-type, but for the other variants, there was no extracellular secretion, and it had nearly all been degraded inside the cell within six hours. Results from pulse-chase analysis using proteasome inhibitors also showed that intracellular degradation of mutant protein was inhibited. Activity of the A139V variant was decreased to 71% of wild-type, and the phospholipid binding capacity fell to as low as 45%. These results suggest that although the A139V variant has normal secretion, it has abnormal phospholipid binding capacity, and therefore causes type II PS deficiency, in which PS activity is decreased. It is also thought that with the other variants, misfolding due to amino acid mutations causes nearly all PS to be degraded intracellularly, therefore leading to type I PS deficiency. |
[Mh] Termos MeSH primário: |
Proteínas Sanguíneas/genética Mutação da Fase de Leitura Mutação de Sentido Incorreto Deficiência de Proteína S/genética Proteína S/genética
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[Mh] Termos MeSH secundário: |
Adolescente Adulto Grupo com Ancestrais do Continente Asiático/genética Proteínas Sanguíneas/metabolismo Feminino Genótipo Seres Humanos Japão/epidemiologia Masculino Fosfolipídeos/metabolismo Ligação Proteica Proteína S/metabolismo Deficiência de Proteína S/epidemiologia Deficiência de Proteína S/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Blood Proteins); 0 (PROS1 protein, human); 0 (Phospholipids); 0 (Protein S) |
[Em] Mês de entrada: | 1704 |
[Cu] Atualização por classe: | 170428 |
[Lr] Data última revisão:
| 170428 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170116 |
[St] Status: | MEDLINE |
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