Haemophilia B: database of point mutations and short additions and deletions--third edition, 1992

Abstract

The data base below lists known point mutations and short deletions and additions in the factor IX gene, causing the bleeding disorder haemophilia B or Christmas disease (for reviews, see Brownlee 1988, Giannelli 1989, Thompson 1990, Green et al 1991a These mutations result in a defective clotting factor IX-a glycoprotein of 415 amino acid residues normally present in plasma and an essential component of the clotting cascade. The disease is an X-linked inherited recessive disorder affecting 1 in about 30,000 males and only very rarely females.The purpose of this database is to update last year's one (Giannelli et al, 1991) by collecting in an accessible, summary form, molecular data on the causative mutations of haemophilia B patients worldwide. It is not intended to replace primary publications although it does contain a significant amount of unpublished work. As in previous years, we have included r observations of the same mutation, as well as molecularly unique mutations. We have continued our database numbering system (Giannelli et al (1991) giving all patients a unique Patient Identity Number (PIN or ID number).The factor IX gene lies on the long arm of the x chromosome at Xq27 and its entire sequence of 33 kb is known (Yoshitake et al, 1985). It contains 8 exons (a-h) encoding 6 major domains of factor IX. These are: (1) exon a-a hydrophobic signal peptide which targets the protein for secretion from the hepatocyte into the blood stream. (2) exons b and c-a propeptide and gla domain,-the latter containing 12 -y-carboxyglutamyl residues. This post-translational modification is required for the correct folding and calcium binding of factor IX. (3) exon d-a type B, or first epidermal growth factor-like domain, which shows homology to epidermal growth factor (EGF) and, in addition, contains conserved carboxylate residues including a ,hydroxyaspartate at amino acid 64. This domain binds an additional Ca2+ with high affinity (Handford et al, 1991). ( 4) exon e-a type A, or second epidermal growthfactor-like (EGF) domain which lacks the conserved carboxylate residues of the EGF type B domain. (5) exon f-an activation domain, within which factor XIa cleaves twice, converting factor IX to IXa; (6) exons g and h-the serine protease or catalytic domain, responsible for the proteolysis of factorxto Xa. This region is homologous to other well studied serine proteases (e.g. chymotrypsin) and it is thought likely that his (221), asp (269) and ser (365), all participate in the classical catalytic mechanism.Factor IX is initially synthesised in the liver as a precursor molecule, either 46, 41 or 39 amino acids (it is not known which, although 39 is probable (Pang et al, 1990)) longer at its Nterminus than the 415-long mature factor IX found in plasma. Processing steps occur in the hepatocyte prior to secretion and sequentially remove the hydrophobic signal peptide and the propeptide. In addition to the -y-carboxylation of the 12 N-terminal glutamyl residues carried out by a vitamin K-dependent carboxylase, and the parti...

Hereditary angioedema in Greek families caused by novel and recurrent mutations

“…Regarding the SERPING1 gene, there is only one report describing the dinucleotide mutation g.8502_ 03TCϾAA in SERPING1, resulting in the missense mutation V233E [18]. Considering other genes and diseases, Giannelli et al reported that the dinucleotide mutation TAϾCG, resulting in amino acid substitution S365G, in factor IX gene caused hemophilia B [19]. By contrast, three more records with dinucleotide substitutions were present in the Hemophilia B Mutation Database (http://www.kcl.ac.…”

Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I.

“…However, a very similar mutation in donor splice junction of intron 2 in PS 06 does not seem to lead to splicing problems. On the other hand, mutations of position +5 in the intervening sequence have been implicated in, e.g., protein C deficiency and hemophilia B (34,35).…”

Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes.

“…Angela Christiano and Jouni Uitto of the Department of Dermatology, Jefferson Medical College, provided PCR products from the COL7A1 gene (35). Steve Sommer (Mayo Clinic, Rochester, MN) provided PCR products from the factor IX-encoding gene (36).…”