Characterization of five partial deletions of the factor VIII gene.

Abstract

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; (it) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (ii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliiminates 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.

A deletion involving intron 13 and exon 14 of factor VIII gene in a haemophiliac with anti-factor VIII antibody

“…As far as the gene deletion of exon 14 is concerned, a small deletion of 2.5 kbp or 2.0-2.5 kbp was not involved in the occurrence of an antibody (inhibitor) against factor VIII (Youssoufian et al, 1987a;Higuchi et al, 1987). However, a large deletion of 12-14 kbp containing exon 14 caused inhibitor (Higuchi et al, 1987).…”

“…The genetic heterogeneity of haemophilia patients suggests that many different molecular alterations are involved in the resultant malfunctional factor VIII gene in haemophiliacs. Several point and deletion mutations in the factor VIII gene were observed in Caucasian population (Gitschier et al, 1985(Gitschier et al, , 1986Antonarakis et al, 1985;Youssoufian et al, 1986Youssoufian et al, , 1987aYoussoufian et al, , 1987bHiguchi et al, 1987;Bernardi et aL, 1987;Matthews et al, 1987).…”

Ready, Steady, Go—The Current State of Carriership Status Determination and Prenatal Diagnosis of Haemophilia a in Bulgaria

“…in the remaining half of the patients with functional factor Viii levels < 1 %, as well as in moderate and mild haemophilia, the causative mutation is, most often, a point mutation or a small gene rearrangement (inversion, deletion, etc). Deletions of any exon of the Factor Viii gene except for exon 22 (which is deleted in-frame) produces severe haemophilia A, as it usually results in disruption of the reading frame beyond the deletion site (54). in any case, the gene for Factor Viii does not have a prominent mutation hotspot and, respectively, most patients in which the causative mutation is not the large inversion with breakpoints in the intron 22 repeated region do carry their own private mutation (51).…”

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“…However, this type of analysis is complicated in this disease because the gene is one of the largest ones in the human genome, and most mutations consists of single nucleotide substitutions, small deletions, and insertions expanded along the gene. Almost every patient has a different mutation [3,4]. In view of these problems, indirect detection using polymorphic markers associated with the factor VIII locus is the best option.…”