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Identification and characterization of two novel mutations (Q421 K and R123P) in congenital factor XII deficiency

Academic Article
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Overview

authors

  • Kanaji, Taisuke
  • Kanaji, S.
  • Osaki, K.
  • Kuroiwa, M.
  • Sakaguchi, M.
  • Mihara, K.
  • Niho, Y.
  • Okamura, T.

publication date

  • December 2001

journal

  • Thrombosis and Haemostasis  Journal

abstract

  • The factor XII genes of two unrelated factor XII-deficient Japanese families were screened, and two novel mutations were identified. A heterozygous mutation (Q421K) was identified in the gene of a cross-reacting material (CRM)-negative patient with reduced FXII activity (entitled Case 1). No mutations were discovered in the other allele. Case 2 was a CRM-negative patient with severe FXII deficiency. In this case, a homozygous mutation (R123P) was discerned. Expression studies in Chinese Hamster Ovary (CHO) cells demonstrated accumulation of mutant Q421 K factor XII in the cell, and insufficient secretion, while the R123P mutant showed lower levels of accumulation than wild-type, and no evidence of secretion in culture supernatant. In the presence of proteasome inhibitor, all types of FXII (wild-type. Q421K, R123P) accumulated in the cells. Protease protection experiments using the microsomal fraction of these cell lines demonstrated that while 20% wild-type FXII (total wild-type:100%) and 10% R123P mutant (total R123P-type: 40%) were resistant to treatment with trypsin, 50% Q421K-type FXII (total Q421K-type:130%) remained resistant to digestion. From these results, we conclude that Q421K is less susceptible to proteasome degradation than wild-type, but is unable to exit the ER efficiently, resulting in insufficient secretion phenotype. In contrast, R123P is susceptible to proteasome degradation and is not secreted.

subject areas

  • Acetylcysteine
  • Adolescent
  • Amino Acid Substitution
  • Animals
  • Brefeldin A
  • CHO Cells
  • Codon
  • Cricetinae
  • Cricetulus
  • Cysteine Endopeptidases
  • DNA Mutational Analysis
  • Exons
  • Factor XII
  • Factor XII Deficiency
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Multienzyme Complexes
  • Mutation, Missense
  • Partial Thromboplastin Time
  • Pedigree
  • Point Mutation
  • Polymerase Chain Reaction
  • Protease Inhibitors
  • Proteasome Endopeptidase Complex
  • Recombinant Fusion Proteins
  • Transfection
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Research

keywords

  • FXII deficiency
  • mutation
  • proteasome
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Identity

International Standard Serial Number (ISSN)

  • 0340-6245

PubMed ID

  • 11776307
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Additional Document Info

start page

  • 1409

end page

  • 1415

volume

  • 86

issue

  • 6

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