Showing papers by "Stylianos E. Antonarakis published in 1986"

Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots

Abstract: Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII1 It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations2 The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors3 Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A Indeed, of the nine mutations described to date, all appear to be unique changes4–6 However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather These observations strongly support the view that CpG dinucleotides are mutation hotspots

On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups

Abstract: Seven beta-thalassemia genes were characterized after they were identified as candidates for previously undescribed mutations based upon the close association of DNA polymorphism haplotypes in the beta-globin gene cluster with specific ethnic mutations. The molecular defect in four of these genes was identical, a frameshift deletion of four nucleotides (-CTTT) within codons 41 and 42. This gene represents a common Southeast Asian mutation shared by a Laotian beta-thalassemia gene, [framework 1 (FR1)], a Vietnamese (FR1), and two Chinese patients (FR3 Asian and FR1). The deletion has been observed previously in Chinese (FR1) and Asian Indians (FR2) and is an example of independent origins of the same molecular defect, possible interallelic gene conversion (as it is seen on two different beta-globin gene frameworks in Chinese), and mutant gene migration in the Asian countries. A second example of mutant gene migration was identified in an Iranian patient with a nucleotide insertion (G) between codons 8 and 9, the same mutation previously found in an Asian Indian in the same chromosomal background. The last two genes examined represent further strong evidence for independent origins of mutation. A C-to-T substitution at position -88 in an Asian Indian has been identified previously in an American Black on a different beta-globin gene framework, and a G-to-A transition at nucleotide 1 of intervening sequence 2 found in an American Black has been observed previously on a different chromosome background in Mediterraneans. This study suggests that there are not many common beta-thalassemia mutations remaining to be discovered. It also suggests that certain sequences in the beta-globin gene are relatively mutation sensitive.

Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4).

Abstract: The genes coding for three proteins of the plasma lipid transport system--apolipoproteins A1 (APOA1), C3 (APOC3), and A4 (APOA4)--are closely linked and tandemly organized on the long arm of human chromosome 11. In this study the human APOA4 gene has been isolated and characterized. In contrast to APOA1 and APOC3 genes, which contain three introns, the APOA4 gene contains only two. An intron interrupting the 5' noncoding region of the APOA1 and APOC3 mRNAs is absent from the corresponding position of the APOA4 mRNA. However, similar to APOA1 and APOC3 genes, the introns of the APOA4 gene separate nucleotide sequences coding for the signal peptide and the amphipathic domains in APOA4. These results suggest that the APOA1, APOC3, and APOA4 genes were derived from a common evolutionary ancestor and indicate that during evolution the APOA4 gene lost one of its ancestral introns. Two restriction endonuclease sites, an Xba I located in the second intron of the APOA4 gene and a different Xba I located 9 kilobases 3' to the APOA4 gene, are polymorphic in Mediterranean and Northern European populations. Haplotype analysis indicated that even though these polymorphic sites are located within 9 kilobases they do not display significant nonrandom association. Finally, restriction mapping analysis of DNA from a patient with combined APOA1-APOC3 deficiency and premature coronary artery disease indicated that this patient has a structurally normal APOA4 gene.

Familial isolated aniridia associated with a translocation involving chromosomes 11 and 22 [t(11;22)(p13;q12.2)].

Abstract: Isolated aniridia segregated as an autosomal dominant trait in a family with 11 affected members spanning five generations. Four of the eight individuals studied had aniridia associated with glaucoma and cataracts. Cytogenetic studies revealed an apparently balanced reciprocal translocation between chromosomes 11 and 22 [t(11;22)(p13;q12.2)], while four unaffected relatives had normal karyotypes. There is no evidence of Wilms tumor or genitourinary abnormalities in any members of the family. Restriction enzyme analysis of the human catalase gene revealed no abnormalities in the individuals with the translocation. A summary of phenotypic abnormalities in 61 cases associated with aniridia is presented, as well as a comparison of breakpoints in 44 cases of 11p deletion. These data indicate that single breaks at 11p13 are associated with isolated aniridia, while deletion of 11p13 results in aniridia combined with Wilms tumor, genitourinary abnormalities, and/or mental retardation.

The same "TATA" box β-thalassemia mutation in Chinese and US blacks: another example of independent origins of mutation

Abstract: A Chinese beta +-thalassemia gene in a new haplotype was chosen for cloning and sequencing. The mutation identified was an A-G transition at position -29 in the TATA box of the beta-globin gene. This mutation has not been seen previously in Chinese but has been documented in American blacks on a different chromosomal background. This observation provides further evidence for independent origins of the same mutation in distinct ethnic groups.