First report of molecular diagnosis of Tunisian hemophiliacs A: Identification of 8 novel causative mutations

Autor: Kaouther Zahra, Amel Ben Ammar Elggaaied, Balkis Meddeb, Hejer Elmahmoudi, Christine Vinciguerra, Emna Gouider, Asma Jlizi, Houssein Khodjet-El-Khil, Edvard Wigren, Dorothé Pellechia
Rok vydání: 2012
Předmět:
Models
Molecular
Protein Conformation
DNA Mutational Analysis
medicine.disease_cause
Polymerase Chain Reaction
Severity of Illness Index
Hemorrhagic disorder
Exon
hemic and lymphatic diseases
Databases
Genetic
Missense mutation
Child
X-linked recessive inheritance
Sequence Deletion
Genetics
Mutation
Intron 1 inversion
Exons
General Medicine
Blotting
Southern
Phenotype
Child
Preschool
Mutations
Intron 22 inversion
lcsh:RB1-214
Adult
Tunisia
Histology
Adolescent
Mutation
Missense
Biology
Hemophilia A
Pathology and Forensic Medicine
Structure-Activity Relationship
Young Adult
lcsh:Pathology
medicine
Humans
Point Mutation
Genetic Predisposition to Disease
Gene
Factor VIII
Inhibitors
Sequence Inversion
Research
Molecular analysis
Point mutation
Intron
Computational Biology
Introns
Mutagenesis
Insertional
Zdroj: Diagnostic Pathology
Diagnostic Pathology, Vol 7, Iss 1, p 93 (2012)
ISSN: 1746-1596
DOI: 10.1186/1746-1596-7-93
Popis: Introduction Hemophilia A is an X linked recessive hemorrhagic disorder caused by mutations in the F8 gene that lead to qualitative and/or quantitative deficiencies of coagulation factor VIII (FVIII). Molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. Molecular studies of these mutations are essential in order to reinforce our understanding of their pathogenic effect responsible for the disorder. Aim In this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum. Methods We screened the presence of intron 22 and intron 1 inversion in severe hemophilia A patients by southern blotting and polymerase chain reaction (PCR). Detection of point mutations was performed by dHPLC/sequencing of the coding F8 gene region. We predict the potential functional consequences of novel missense mutations with bioinformatics approaches and mapping of their spatial positions on the available FVIII 3D structure. Results We identified 23 different mutations in 28 Tunisian hemophilia A patients belonging to 22 unrelated families. The identified mutations included 5 intron 22 inversions, 7 insertions, 4 deletions and 7 substitutions. In total 18 point mutations were identified, of which 9 are located in exon 14, the most mutated exonic sequence in the F8 gene. Among the 23 mutations, 8 are novel and not deposited in the HAMSTeRS database nor described in recently published articles. Conclusion The mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715
Databáze: OpenAIRE
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