Creation of a novel donor splice site in intron 1 of the factor VIII gene leads to activation of a 191 bp cryptic exon in two haemophilia A patients

被引:42
作者
Bagnall, RD
Waseem, NH
Green, PM
Colvin, B
Lee, C
Giannelli, F
机构
[1] Guys Kings & St Thomas Sch Med, Div Med & Mol Genet, London SE1 9RT, England
[2] Royal London Hosp, Dept Haematol, Haemophilia Ctr, London E1 1BB, England
[3] Royal Free Hosp, Haemophilia Ctr, London NW3 2QG, England
关键词
haemophilia A; cryptic exon; mRNA analysis; mutation detection; haplotype analysis;
D O I
10.1046/j.1365-2141.1999.01767.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We have constructed a confidential U.K, database of haemophilia A mutations and pedigrees by characterizing the gene defect of one index patient in each U.K, family. Mutations were identified by screening all coding regions of the factor VIII (FVIII) mRNA, using solid-phase fluorescent chemical cleavage of mismatch and examining additional non-coding regions of the gene. Here we report two haemophilia A patients (UK 114 FVIII:C 2% and UK 243 FVIII:C <1%) with an abnormal FVIII mRNA due to an A to G point mutation, 1.4 kb downstream from exon 1 in the FVIII gene. This mutation creates a new donor splice site intron 1 and leads to insertion of a 191 bp novel exon in the mRNA. Haplotype analysis suggests that the mutation may have originated in a common ancestor of the two patients, who further illustrate how mRNA analysis allows higher efficiency of haemophilia A mutation detection, because their mutation would not have been identified by direct analysis of the factor VIII gene.
引用
收藏
页码:766 / 771
页数:6
相关论文
共 26 条
  • [1] Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia
    Brinke, A
    Tagliavacca, L
    Naylor, J
    Green, P
    Giangrande, P
    Giannelli, F
    [J]. HUMAN MOLECULAR GENETICS, 1996, 5 (12) : 1945 - 1951
  • [2] CHILLON M, 1995, AM J HUM GENET, V56, P623
  • [3] A G→A transition creates a branch point sequence and activation of a cryptic exon, resulting in the hereditary disorder neurofibromatosis 2
    De Klein, A
    Riegman, PHJ
    Bijlsma, EK
    Heldoorn, A
    Muijtjens, M
    den Bakker, MA
    Avezaat, CJJ
    Zwarthoff, EC
    [J]. HUMAN MOLECULAR GENETICS, 1998, 7 (03) : 393 - 398
  • [4] CHARACTERIZATION OF THE HUMAN FACTOR-VIII GENE
    GITSCHIER, J
    WOOD, WI
    GORALKA, TM
    WION, KL
    CHEN, EY
    EATON, DH
    VEHAR, GA
    CAPON, DJ
    LAWN, RM
    [J]. NATURE, 1984, 312 (5992) : 326 - 330
  • [5] A NOVEL MUTATION IN THE CYSTIC-FIBROSIS GENE IN PATIENTS WITH PULMONARY-DISEASE BUT NORMAL SWEAT CHLORIDE CONCENTRATIONS
    HIGHSMITH, WE
    BURCH, LH
    ZHOU, ZQ
    OLSEN, JC
    BOAT, TE
    SPOCK, A
    GORVOY, JD
    QUITTELL, L
    FRIEDMAN, KJ
    SILVERMAN, LM
    BOUCHER, RC
    KNOWLES, MR
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1994, 331 (15) : 974 - 980
  • [6] HIGUCHI M, 1991, P NATL ACAD SCI USA, V88, P405
  • [7] Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors
    Hoffmeyer, S
    Nürnberg, P
    Ritter, H
    Fahsold, R
    Leistner, W
    Kaufmann, D
    Krone, W
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (02) : 269 - 277
  • [8] The Factor VIII Structure and Mutation Resource Site: HAMSTeRS Version 4
    Kemball-Cook, G
    Tuddenham, EGD
    Wacey, AI
    [J]. NUCLEIC ACIDS RESEARCH, 1998, 26 (01) : 216 - 219
  • [9] INVERSIONS DISRUPTING THE FACTOR-VIII GENE ARE A COMMON-CAUSE OF SEVERE HEMOPHILIA-A
    LAKICH, D
    KAZAZIAN, HH
    ANTONARAKIS, SE
    GITSCHIER, J
    [J]. NATURE GENETICS, 1993, 5 (03) : 236 - 241
  • [10] HEMOPHILIA-A DIAGNOSIS BY ANALYSIS OF A HYPERVARIABLE DINUCLEOTIDE REPEAT WITHIN THE FACTOR-VIII GENE
    LALLOZ, MRA
    MCVEY, JH
    PATTINSON, JK
    TUDDENHAM, EGD
    [J]. LANCET, 1991, 338 (8761) : 207 - 211