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

We studied a 29-year-old Japanese male patient with factor XI deficiency; w e also studied his parents and one sibling. Factor XI coagulation activity and antigen levels were extremely low (less than 1% of normal level) in bot h 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 non sense mutation in exon 8 (Gln(263)-->Stop). Although the parents are first cousins, the mutation was unexpectedly heterozygous in all the family membe rs except the father, who showed the homozygous wild type, indicating that this mutation alone was not sufficient to account for the factor XI deficie ncy. To explore the genetic abnormality in the father, we analyzed allele-s pecific expression of the platelet factor XI gene using reverse transcripti on-polymerase chain reaction and subsequent restriction enzyme digestion. A s a result, gene expression from only one allele was severely impaired in t he father. This result implies an additional mutation in some regulatory el ement of the factor XI gene from paternal inheritance. We concluded that th e factor XI deficiency of the patient was caused by compound heterozygous g enetic abnormalities. (C) 2000 The Japanese Society of Hematology.