title: Small FVIII gene rearrangements in 18 hemophilia A patients: five novel mutations.
abstract: Hemophilia A (HA) is a disorder caused by mutations of the FVIII gene, which is located on the tip of the long arm of the X chromosome. In a cohort of 18 unrelated Italian patients affected with HA of varying severity, we performed mutational screening of the gene by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of abnormal peaks. We identified five novel mutations and 9 previously reported DNA alterations. Two of the 9 previously reported alterations were each common to 3 unrelated patients. Six different mutations were characterized as missense alterations, while 8 were non-missense mutations. Among the new gene alterations, one created a stop codon, one consisted of an out-of frame deletion, and one was a splice-site mutation. The last two were missense alterations. In an attempt to better understand the causative effect of the mutations and the clinical variability of the patients, we investigated the consequences of each missense mutation and visualized the effect of the amino acid change on structural FVIII models.
authors.affiliation: Department of Hematology and Oncology, Thrombosis and Hemostasis Unit, Giannina Gaslini Institute, Genova, Italy.
authors.forename: Maria Patrizia
authors.initials: MP
authors.lastname: Bicocchi
authors.forename: Mirella
authors.initials: M
authors.lastname: Pasino
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lanza
authors.forename: Federico
authors.initials: F
authors.lastname: Bottini
authors.forename: Angelo Claudio
authors.initials: AC
authors.lastname: Molinari
authors.forename: Daniela
authors.initials: D
authors.lastname: Caprino
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.forename: Maura
authors.initials: M
authors.lastname: Acquila
mesh_terms: D018389:Codon, Nonsense; D004252:DNA Mutational Analysis / Q000379:methods; D005167:Factor VII / Q000737:chemistry / Q000235:genetics*; D015321:Gene Rearrangement; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007558:Italy; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense / Q000502:physiology; D010641:Phenotype; D011487:Protein Conformation; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D005167:Factor VII