A novel type of factor XI deficiency showing compound genetic abnormalities: a nonsense mutation and an impaired...

We studied a 29-year-old Japanese male patient with factor XI deficiency; we also studied his parents and one sibling. Factor XI coagulation activity and antigen levels were extremely low (less than 1% of normal level) in both the patient and his brother, and they were half the normal levels in both parents. Sequence analysis of all 15 exons and the exon-intron boundaries of the factor XI gene amplified by polymerase chain reaction revealed a nonsense mutation in exon 8 (Gln263-->Stop). Although the parents are first cousins, the mutation was unexpectedly heterozygous in all the family members except the father, who showed the homozygous wild type, indicating that this mutation alone was not sufficient to account for the factor XI deficiency. To explore the genetic abnormality in the father, we analyzed allele-specific expression of the platelet factor XI gene using reverse transcription-polymerase chain reaction and subsequent restriction enzyme digestion. As a result, gene expression from only one allele was severely impaired in the father. This result implies an additional mutation in some regulatory element of the factor XI gene from paternal inheritance. We concluded that the factor XI deficiency of the patient was caused by compound heterozygous genetic abnormalities.