Characterization of Five Partial Deletions of the Factor VIII Gene

• Published in: Proceedings of the National Academy of Sciences - PNAS 1987-06, Vol.84 (11), p.3772-3776
• Main Authors: YOUSSOUFIAN, H, ANTONARAKIS, S. E, ARONIS, S, TSIFTIS, G, PHILLIPS, D. G, KAZAZIAN, H. H. JR
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chromosome Deletion; Classical genetics, quantitative genetics, hybrids; DNA; DNA probes; DNA Restriction Enzymes; Exons; Factor VIII - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene deletion; Genes; Genetic Carrier Screening; Genetic mutation; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Hemophilia A; Hemophilia A - blood; Hemophilia A - genetics; Human; Humans; Introns; Lawns; Male; Pedigree; Point mutation; Polymorphism, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.84.11.3772

Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, we have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5′sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes.