Some factor VIII exon 14 frameshift mutations cause moderately severe haemophilia A

• Published in: British journal of haematology 2001-12, Vol.115 (4), p.977-982
• Main Authors: Nakaya, Shelley, Liu, Miao‐Liang, Thompson, Arthur R.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Child; Child, Preschool; exon 14; Exons; factor VIII; Factor VIII - genetics; Female; Frameshift Mutation; frameshift mutations; haemophilia A; Hematologic and hematopoietic diseases; Hemophilia A - genetics; Heteroduplex Analysis; Humans; Male; Medical sciences; Middle Aged; Platelet diseases and coagulopathies
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.2001.03173.x

Factor VIII's exon 14 codes for its B domain that includes nearly one‐third of its amino acid sequence that is not necessary for function. Frameshift mutations appear to occur more frequently within exon 14 than in other exons. To assess exon 14 frameshift mutations and their clinical correlates, a series of unrelated, severe or moderately severe haemophilia A patients were screened for heteroduplex formation in amplified exon 14 fragments. In 25 families, a frameshift mutation was identified by sequencing. Occurrence of haemophilia was isolated in 18 of these families. Moderate severity was noted in at least six out of 13 families with an A insertion or deletion at one of two sequences where the frameshift resulted in a sequence of 8–10 As. Inhibitors occurred in five of the other 12 families including one with an A insertion within a sequence of six As. Recurrent insertions into an A8 (codons 1439–1441) or an A9 (codons 1191–1194) sequence or of an A deletion from the A9 sequence are common, recurrent causes of haemophilia A that may have a moderately severe phenotype.