IDENTIFICATION OF MUTATIONS AND POLYMORPHISMS IN THE FACTOR-XI GENES OF AN AFRICAN-AMERICAN FAMILY BY DIDEOXYFINGERPRINTING

Congenital deficiency of factor XI is a rare condition associated with a mild to moderate bleeding diathesis that is most commonly found in persons of Jewish ancestry. The disorder has been reported sporadicall y in a number of other ethnic groups, but rarely in the black populati on. We report on the genetic analysis of the factor XI genes of two Af rican American patients: a 9-year-old boy (the propositus) with mild f actor XI deficiency and his mother. Both individuals have lifelong his tories of excessive bleeding. Dideoxyfingerprinting, a technique combi ning components of single-strand conformational polymorphism analysis and dideoxy-chain termination sequencing, was used in the analysis. Bo th patients were found to be heterozygous for a mutation changing seri ne 248 to glutamine, whereas the propositus was heterozygous for an ad ditional mutation on the paternal allele changing glutamine 226 to arg inine. Both mutations reside in the third apple domain of the factor X I heavy chain, an area that has been shown to contain binding sites fo r factor IX, platelets, and glycosaminoglycans. Previously reported mu tations in the factor XI gene seem to cause deficiency primarily by re ducing protein expression. Because both alleles in the propositus cont ain amino acid substitutions, the significant amount of circulating fa ctor XI in his plasma must be comprised entirely of abnormal molecules . Factor XI circulates as a homodimer, and the presence of mutations i n both alleles of the factor XI gene suggests that his bleeding disord er is caused in part by the effect of the two abnormal gene products f orming dimers in different combinations. Three neutral (not associated with amino acid changes) DNA polymorphisms were also identified in th e two subjects: a C to T change at nucleotide 472 in exon 5, A to G at nucleotide 844 in exon 8, and T to C at nucleotide 1234 in exon 11. A nalysis of a random sample of normal volunteers showed that these poly morphisms are relatively common, with allele frequencies of 7.4%, 19%, and 18%, respectively. This suggests that there is considerable genet ic heterogeneity in the factor XI gene. (C) 1998 by The American Socie ty of Hematology.