Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping

William C. Nichols, Uri Seligsohn, Ariella Zivelin, Valeri H. Terry, Nathan D. Arnold, David R. Siemieniak, Randal J. Kaufman, David Ginsburg

Research output: Contribution to journalArticlepeer-review

Abstract

Combined Factors V and VIII deficiency is an autosomal recessive bleeding disorder identified in at least 58 families comprising a number of different ethnic groups. Affected patients present with a moderate bleeding tendency and have Factor V and Factor VIII levels in the range of 5-30% of normal. The highest frequency of the mutant gene is found in Jews of Sephardic and Middle Eastern origin living in Israel with an estimated disease frequency of 1: 100,000. We sought to identify the gene responsible for combined Factors V and VIII deficiency using a positional cloning approach. Of 14 affected individuals from 8 unrelated Jewish families, 12 were the offspring of first-cousin marriages. After a genome-wide search using 241 highly polymorphic short tandem repeat (STR) markers, 13 of the 14 affected patients were homozygous for two closely linked 18q markers. Patients and all available family members were genotyped for 11 additional STRs spanning ~11 cM on the long arm of chromosome 18. Multipoint linkage analysis yielded a maximal log of the odds (LOD) score of 13.22. Haplotype analysis identified a number of recombinant individuals and established a minimum candidate interval of 2.5 cM for the gene responsible for combined Factors V and VIII deficiency. The product of this locus is likely to operate at a common step in the biosynthetic pathway for these two functionally and structurally homologous coagulation proteins. Identification of this gene should provide new insight into the biology of Factor V and Factor VIII production.

Original languageEnglish
Pages (from-to)596-601
Number of pages6
JournalJournal of Clinical Investigation
Volume99
Issue number4
DOIs
StatePublished - 15 Feb 1997

Keywords

  • Jewish
  • bleeding disorder
  • coagulation Factors
  • gene
  • hemophilia

Fingerprint

Dive into the research topics of 'Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping'. Together they form a unique fingerprint.

Cite this