The sixth edition of the haemophilia B database lists in easily accessible form all known factor IX mutations due to small changes (base substitutions and short additions and/or deletions of <30 bp) identified in haemophilia B patients. The 1380 patient entries are ordered by the nucleotide number of their mutation. Where known, details are given on factor IX activity, factor IX antigen in circulation and origin of mutation. References to published mutations are given and the laboratories generating the data are indicated.

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The families of sporadic haemophilia A patients registered at the Royal London Hospital and with living grandparents were selected for study. Twelve of the 13 known families agreed to collaborate. Of these 11 had a patient with severe and one a patient with mild haemophilia. Five of the severely affected patients had inversions of type 1, that is involving int22h-1 and int22h-3, and two had inversions of type 2, that is involving int22h-1 and int22h-2. The remaining four patients with severe disease had single base substitutions causing two different non-sense (Gln592→Stop; Trp2313→Stop) and two different mis-sense mutations (His267→Pro; Arg2209→Gln). A single base substitution causing a mis-sense mutation (His1961→Asp) was also found in the patient with mild haemophilia. The Arg2209→Gln mutation has previously been found in other patients while the other single base substitutions have not hitherto been observed. Three mutations (all single base substitutions) appear to have arisen in the germline of the patient's mother, while seven mutations originated in the gonad of one of the patient's grandparents. In two of the latter families (both with inversion type 2) the origin of muta-tions could be clearly assigned to the grandpaternal gonad. Data on parental age at the onset of mutation were ob-tained in the families investigated. In addition, further evidence was obtained that the int-22h-related inversions arise by intrachromatid, intrachromosome homologous re-combination as the int22h repeat sequences of a patient were found to be identical to those of the maternal grand-father whose germline represents the origin of mutation.

In the course of analysing mutation in the factor IX gene from 200 haemophilia B patients in Sweden and the UK, we have identified one patient with a prepeptide missense mutation. He has severe, antigen negative haemophilia, and complete analysis of his coding sequence reveals a single base transversion (A-->T) causing substitution of isoleucine by asparagine at position -30. This change disrupts the hydrophobic core of the prepeptide, a feature which is required for secretion. Thus, haemophilia in this patient is caused by a failure to secrete factor IX from the hepatocytes.

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