largely subjective alteration in the natural resolution of herpes simplex labialis worthwhile? The decision of those in charge of a health system with finite resources that has to meet the demands of a whole range of patients, some with life-threatening illnesses, may not be the same as that reached by a patient suffering from the pain and discomfort of a cold


Where does this leave clinicians?

1. Fiddian

AP, Yeo JM, Stubbings R, Dean D. Successful treatment of herpes labialis with topical acyclovir. Br Med J 1983; 286: 1699-701. 2. Raborn GW, McGaw WT, Grace M, Percy J, Samuels S. Herpes labialis with acyclovir 5% modified aqueous cream: a double blind randomised trial. Oral Surg Oral Med Oral Pathol 1989; 67: 676-79. 3. Raborn GW, McGaw WT, Grace M, Houle L. Herpes labialis treatment with acyclovir 5 per cent ointment. Can Dent Assoc J 1989; 55: 135-37. 4. Spruance SL, Hamill ML, Hoge WS, Davis LG, Mills J. Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA 1988; 260: 1597-98. 5. Spruance SL, Stewart JCB, Rowe NH, McKeough MB, Wenerstrom G, Freeman DJ. Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 1990; 161: 185-90. 6. Spruance SL, Stewart JCB, Freeman DJ, et al. Early application of topical 15% idoxuridine in dimethyl sulfoxide shortens the course of herpes simplex labialis: a multicenter placebo-controlled trial. J Infect Dis 1990; 161: 191-97. 7. Lawee D, Rosenthal D, Akoi FY, Portnoy J. Efficicency and safety of foscarnet for recurrent orolabial herpes: a multi-centre randomized double-blind study. Can Med Assoc J 1988; 138: 329-33. 8. Glezerman M, Lunenfeld E, Cohen V, et al. Placebo-controlled trial of topical interferon in labial and genital herpes. Lancet 1988; i: 150-52. treatment

MOLECULAR BASIS OF ABO POLYMORPHISM The first steps in understanding the molecular basis of the ABO histo-blood group system have been reported by Yamamoto and colleagues in Seattle.1 The ABO antigens were first described by Landsteiner in 1900 as red cell antigens; ABO compatible blood is a basic requirement for safe transfusion. ABO determinants are carbohydrate with characteristic antigens, oligosaccharides immunodominant sugars whose structures and biosynthetic pathways were determined by Morgan and Watkins2 and by Kabat.3 Although carbohydrate antigens cannot be primary gene products, the ABO antigens are inherited in a simple mendelian manner. Morgan and Watkins suggested that A and B genes encode glycosyltransferases (alpha 1-3 N-acetyl-D-galactosaminyl and alpha 1-+3 D-galactosyl transferases, respectively) which transfer specific sugars from activated donor substrates to an acceptor precursor molecule. The 0 gene does not alter the precursor carbohydrate chain (H antigen) and, therefore, was thought either to be a silent gene or to produce an inactive protein. The molecular organisation of these genes was unknown. organisation of these genes was unknown. Yamamoto et al, using an A-transferase cDNA probe isolated after partial aminoacid sequencing with a human A transferase,4 cloned and sequenced cDNA from four cell lines of different ABO phenotypes to look for sequence differences between the various ABO genes. Several differences were observed but the clones broadly fitted into three types, representing A, B, or 0 cDNA. In comparisons of sequences of predicted A cDNA clones with those of B clones, four nucleotide substitutions were observed consistently. These substitutions led to alteration of four aminoacids. In all predicted 0 cDNA clones the Seattle workers found a single nucleotide deletion (position 258) in the coding region, which causes a shift of the reading frame and, hence, failure to encode a protein similar to the A and B transferases. Except for the deletion, the 0 cDNA sequence was identical to that of an A cDNA sequence.

Despite the initial failure to identify any restriction fragment length polymorphisms (RFLPs) correlating with ABO phenotypes,4 characterisation of the cDNA clones identified specific restriction enzyme cleavage sites at three of the four A:B cDNA substitution sites and at the deletion site found in 0 cDNA.1 Yamamoto et al exploited these findings by using specific RFLP analysis of genomic DNA extracted from buffy coats of fourteen blood samples of known ABO phenotype (four group A, four group B, four group 0, and two group AB). Their results support the molecular genetic basis suggested by the work with cell lines. All group 0 samples had cDNA with the same single deletion at nucleotide position 258. The AB samples had two alleles, called functional alleles because they were devoid of the deletion, and the A and B samples had at least one functional allele. Two critical experiments are required to confirm that the proposed molecular basis is responsible for the ABO polymorphism-chromosomal assignment (the ABO locus is mapped to 9q34’l-q34-2) and demonstration that functional transferases are encoded. Confirmation that the DNAs identified by these techniques carry the sequences necessary to encode functional transferases capable of producing A and B antigens is mentioned by the Seattle group in the discussion, and description of transfection experiments is promised in a future report. The exciting observations of Yamamoto and colleagues, although based on few samples, are convincing. Their hypothesis confirms that A and B genes are indeed alleles. Because of the different specificities of the A and B transferases, the allelic status of their genes was questioned until the transferases were shown to have overlapping specificities and also to be immunologically cross-reactive. At last the action of the 0 gene is explained: it is a non-functional allele because of a structural difference. Knowledge of the molecular basis of the ABO polymorphism opens a new approach to the study of ABO expression. The transferase responsible for At subgroup differs from that for Az subgroup in several kinetic characteristics; Yamamoto et al predict that a few aminoacid differences, additional to those observed for the A:B alleles, could be responsible for this polymorphism. The molecular approach will also help to distinguish and identify the genetic background of many rare ABO phenotypes. Determination of the molecular basis of ABO mosaics should allow easy distinction of people with ABO blood group mosaic phenotypes from those who are true chimaeras. Yamamoto and colleagues believe that DNA analyses will help to elucidate the mechanism causing variation of ABO expression during differentiation and oncogenesis. The ability to genotype A and B individuals will increase the usefulness of the ABO groups as a marker in linkage studies and in forensic invesigations. Description of the number and organisation of the exons and introns of the common and rare ABO alleles is eagerly awaited. F, Clausen H, White T, Marken J, Hakomori S. Molecular genetic basis of the histo-blood group ABO system. Nature 1990; 345:

1. Yamamoto

229-33. 2.

Morgan WTJ, Watkins WM. Genetic and biochemical aspects of human blood-group A-, B-, H-, Lea- and Leb-specificity. Br Med Bull 1969;

25: 30-34. 3. Kabat EA. In: Carbohydrates in solution. Adv Chemistry Series 1973; 117: 334-61. 4. Yamamoto F, Marken J, Tsuji T, White T, Clausen H, Hakomori S. Cloning and characterization of DNA complementary to human UDP-GalNAc: Fuc&agr;1 →2 Gal&agr;1→3 GalNAc transferase (histo-blood group A transferase) mRNA. J Biol Chem 1990; 265: 146-51.

Molecular basis of ABO polymorphism.

1502 largely subjective alteration in the natural resolution of herpes simplex labialis worthwhile? The decision of those in charge of a health syste...
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