کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3027780 1182989 2010 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A novel splice site mutation in intron C of PROS1 leads to markedly reduced mutant mRNA level, absence of thrombin-sensitive region, and impaired secretion and cofactor activity of mutant protein S
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی کاردیولوژی و پزشکی قلب و عروق
پیش نمایش صفحه اول مقاله
A novel splice site mutation in intron C of PROS1 leads to markedly reduced mutant mRNA level, absence of thrombin-sensitive region, and impaired secretion and cofactor activity of mutant protein S
چکیده انگلیسی

Protein S (PS) is a member of the vitamin K-dependent protein family containing similar γ-carboxyglutamic acid (Gla) domains, although only PS has a thrombin-sensitive region (TSR), which is located between the Gla domain and the first epidermal growth factor-like domain. In this study, a novel PROS1 mutation was identified at the last nucleotide in intron C (c.260-1G > A) in a patient suffering from recurrent deep vein thrombosis associated with PS deficiency. To investigate the molecular mechanisms of PS deficiency caused by the novel PROS1 mutation, we characterized the mutant mRNA, and the secretion and function of the mutant PS molecule associated with the mutation. RT-PCR was used to detect the aberrant mRNA in the patient's platelets, the amount of which was markedly reduced and lacked the region corresponding to exon 4 coding the TSR of the PS molecule. The recombinant mutant PS lacking the TSR (TSR-lack PS) showed a markedly reduced transient expression/secretion level, 37.9% of that of wild-type (WT) PS. Activated protein C (APC) cofactor activity assay showed that TSR-lack PS had no cofactor activity. Moreover, binding assays of monoclonal antibodies recognizing the PS Gla domain and the Gla residues indicated that the bindings of TSR-lack PS to both of these antibodies were clearly weaker than those of WT PS. These findings suggest that the novel mutation leading to the absence of the TSR not only affected the secretion of mutant PS, but was also responsible for impairment of the Gla domain conformation required for the γ-carboxylation to express APC cofactor activity.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Thrombosis Research - Volume 125, Issue 5, May 2010, Pages e246–e250
نویسندگان
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