title: Characterization of molecular defects of Fitzgerald trait and another novel high-molecular-weight kininogen-deficient patient: insights into structural requirements for kininogen expression.
abstract: A 6-year-old male with vertebral-basilar artery thrombosis was recognized to have high-molecular-weight kininogen (HK) deficiency. The propositus had no HK procoagulant activity and antigen (< 1%). Using monoclonal antibodies (Mabs) to kininogen domain 3, the propositus, family members, and Fitzgerald plasma were determined to have detectable low-molecular-weight kininogen. Mabs to HK domains 5 and 6 do not detect HK antigen in the propositus' plasma. The propositus has a single base pair (bp) deletion in cDNA position 1492 of exon 10 affecting amino acid 480 of the mature protein and resulting in a frameshift and a premature stop codon at position 1597 (amino acid 532). Unexpectedly, Mabs to the heavy chain and domain 5 of HK detect a 92-kDa form of HK in Fitzgerald plasma, the first HK-deficient plasma. The 92-kDa Fitzgerald HK has amino acid residues through 502, corresponding to domains 1 through 5, but lacks epitopes of domain 6 (positions 543 to 595). Fitzgerald DNA has a normal exon 10, but a 17-bp mutation in intron 9. These combined results indicate that mutations in the kininogen gene may differentially affect biosynthesis, processing, and/or secretion of HK.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0640, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Krijanovski
authors.forename: Valerie
authors.initials: V
authors.lastname: Proulle
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: Marie
authors.initials: M
authors.lastname: Dreyfus
authors.forename: Werner
authors.initials: W
authors.lastname: Müller-Esterl
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
mesh_terms: D002648:Child; D018389:Codon, Nonsense; D005091:Exons; D005192:Family Health; D016368:Frameshift Mutation; D006801:Humans; D015151:Immunoblotting; D007438:Introns; D019679:Kininogen, High-Molecular-Weight / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D007704:Kininogens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008297:Male; D017434:Protein Structure, Tertiary; D013927:Thrombosis / Q000097:blood / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D019679:Kininogen, High-Molecular-Weight; D007704:Kininogens