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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3309-3317
Identification of Mutations and Polymorphisms in the Factor XI
Genes of an African American Family by Dideoxyfingerprinting
Danko Martincic,
Sherri A. Zimmerman,
Russell E. Ware,
Mao-Fu Sun,
James A. Whitlock, and
David Gailani
From the Departments of Pediatrics, Pathology, and Medicine,
Vanderbilt University, Nashville, TN; and the Department of Pediatrics,
Duke University Medical Center, Durham, NC.
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
sporadically in a number of other ethnic groups, but rarely in the
black population. We report on the genetic analysis of the factor XI
genes of two African American patients: a 9-year-old boy (the
propositus) with mild factor XI deficiency and his mother. Both
individuals have lifelong histories of excessive bleeding. Dideoxyfingerprinting, a technique combining components of
single-strand conformational polymorphism analysis and dideoxy-chain
termination sequencing, was used in the analysis. Both patients were
found to be heterozygous for a mutation changing serine 248 to
glutamine, whereas the propositus was heterozygous for an additional
mutation on the paternal allele changing glutamine 226 to arginine.
Both mutations reside in the third apple domain of the factor XI heavy chain, an area that has been shown to contain binding sites for factor
IX, platelets, and glycosaminoglycans. Previously reported mutations in
the factor XI gene seem to cause deficiency primarily by reducing
protein expression. Because both alleles in the propositus contain
amino acid substitutions, the significant amount of circulating factor
XI in his plasma must be comprised entirely of abnormal molecules.
Factor XI circulates as a homodimer, and the presence of mutations in
both alleles of the factor XI gene suggests that his bleeding disorder
is caused in part by the effect of the two abnormal gene products
forming dimers in different combinations. Three neutral (not associated
with amino acid changes) DNA polymorphisms were also identified in the
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. Analysis of a random sample of normal volunteers showed that these
polymorphisms are relatively common, with allele frequencies of 7.4%,
19%, and 18%, respectively. This suggests that there is considerable
genetic heterogeneity in the factor XI gene.
© 1998 by The American Society of Hematology.
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