title: Why does the mutation G17736A/Val107Val (silent) in the F9 gene cause mild haemophilia B in five Swedish families?
abstract: The mutation G17736A/Val107Val (silent) was found in five of a total of 86 families with haemophilia B in Sweden. It is unlikely that five families with analogous clinical expression will have the same polymorphism, which is not found in other patients or normal subjects, or that they will be the only families in the population without any other causative mutation. All affected individuals in the five families were found to have factor IX (F9) coagulation activity 15-20 U dL(-1), corresponding F9 protein levels and the same clinical history of mild haemophilia. Lymphocyte mRNA was extracted from one of the haemophiliacs and from a healthy male. RT-PCR of the mRNA and subsequent PCR amplification produced cDNA fragments of the same length from the patient and the normal subject, indicating no exon skipping or retention of introns. Sequencing of cDNA from codon 68 in exon D to codon 180 in exon F revealed that the patient had the G17736A mutation but no other abnormalities. We conclude that G17736A/Val107Val causes mild haemophilia B. Although, exon skipping and retention of introns can be excluded as pathophysiological mechanisms, it is plausible that the studied mutation has more subtle effects on a splicing site or interferes with a splicing enhancer site. Also, changes to synonymous codons may reduce the translation rate and thereby alter F9 protein folding in vivo, which would explain the phenotype. Confirmation of these assumptions requires methods that are more sensitive than those available today, and our discussion illustrates the existing obstacles.
authors.affiliation: Departments of Paediatrics and Coagulation Disorders, Lund University, University Hospital, Malmö, Sweden. karin.knobe@med.lu.se
authors.forename: K E
authors.initials: KE
authors.lastname: Knobe
authors.forename: E
authors.initials: E
authors.lastname: Sjörin
authors.forename: R C R
authors.initials: RC
authors.lastname: Ljung
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods; D005164:Factor IX / Q000235:genetics*; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D012333:RNA, Messenger; D005164:Factor IX