title: Molecular pathogenesis of plasminogen Hakodate: the second Japanese family case of severe type I plasminogen deficiency manifested late-onset multi-organic chronic pseudomembranous mucositis.
abstract: A 64-year-old man first developed ligneous conjunctivitis at the age of 58 years after right pulmonary resection because of suspected cancer; otherwise, he had been healthy. Since then, he began to suffer from various forms of chronic pseudomembranous mucositis. Laboratory tests demonstrated that he had 7.8 % of plasminogen activity and 5.9 % of the normal antigen level. Thus, he was diagnosed as having severe type I plasminogen deficiency, making him the third case in Japan. DNA sequencing and PCR-restriction fragment length polymorphism analyses revealed that this patient was a compound heterozygote of a G-to-A missense mutation (G266E) in exon VIII and a g-to-a mutation at the obligatory splicing acceptor site in intron 12 (IVS12-1g>a). These two mutations were confirmed to be novel. Molecular modeling and splice site strength calculation predicted conformational disorder(s) for the Glu266 mutant and a drastic decrease in splicing efficiency for intron 12, respectively. Western blot analysis demonstrated that the patient contained a small amount of the normal-sized plasminogen protein. Mass spectrometric analysis of the patient's plasminogen revealed a peptide containing the wild-type Gly266 residue and no peptides with mutations at Glu266. However, he had never suffered from thrombosis. Low levels of fibrinogen/fibrin degradation products (FDP), D-dimer, and plasmin-α2-plasmin inhibitor complex clearly indicated a hypo-fibrinolytic condition. However, his plasma concentration of elastase-digested crosslinked FDPs was 4.8 U/mL, suggesting the presence of an on-going plasmin(ogen)-independent "alternative" fibrinolytic system, which may protect the patient from thrombosis. The patient has been free from recurrence of ligneous conjunctivitis for approximately 2.5 years.
authors.affiliation: Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata, 990-9585, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Osaki
authors.affiliation: Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata, 990-9585, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Souri
authors.affiliation: Department of Ophthalmology, Goryokaku Hospital, Hakodate, Japan.
authors.forename: Young-Seok
authors.initials: YS
authors.lastname: Song
authors.affiliation: Department of Ophthalmology, Goryokaku Hospital, Hakodate, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Izumi
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, VIC, 3800, Australia.
authors.forename: Ruby
authors.initials: R
authors.lastname: Law
authors.affiliation: Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata, 990-9585, Japan. aichinos@med.id.yamagata-u.ac.jp.
authors.forename: Akitada
authors.initials: A
authors.lastname: Ichinose
mesh_terms: D000368:Aged; D002908:Chronic Disease; D003231:Conjunctivitis / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D004761:Enterocolitis, Pseudomembranous; D005342:Fibrinolysis; D006801:Humans; D007564:Japan; D008297:Male; D052016:Mucositis; D020125:Mutation, Missense; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012873:Skin Diseases, Genetic / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*
chemical_list: D022821:RNA Splice Sites; D010958:Plasminogen
keywords: Defective fibrinolysis; Ligneous conjunctivitis; Missense mutation; Plasminogen deficiency; Splicing defect; Systemic pseudomembranous mucositis