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Molecular defects underlying the Kell null phenotype
266 authors concluded that the incubation period is similar in subjects of all ages but that young subjects are more susceptible to infection. Other major assumptions of their model are that individual susceptibility to develop vCJD is constant between 0.5 and 15 years old and then decreases exponentially, that the dose of infectious agent was highest in the early 1980s and decreased with declining number of BSE cases in cattle, and that there is a lognormal distribution of the incubation period. The model of Huillard et al is a more complex back-calculation analysis. Similar to Vallernn et al, assumptions are made that the hazard of infection was proportional to the incidence of BSE in cattle and that the incubation period is independent of the age of the snbject at the time of infection. Huillard et al also assume that only 40% of the United Kingdom population that are homozygous for methionine at codon 129 of the PrP gone are at risk for vCJD because all cases to date have been of this genotype. Valleron et al estimate that the mean incubation period for vCJD is 16.7 years, with a standard deviation of 2.6 years and 95% upper percentile of this distribution at 21.4 years. They project a total cumulative incidence of vCJD of 205 cases, with an upper 95% confidence interval of 403 cases. Huillard et al predicted a cumulative incidence of 900 to 4,000 cases, with a confidence interval of 95%. Both groups point out that if there is another subpopulation of vCJD patients who are not methionine homozygous, these cases would not be identified in their models. Aside from this caveat, the models are more optimistic than previous estimates as to the cumulative incidence of vCJD. Further understanding of the biology of the infectious agent and host susceptibility factors would help refine future epidemiologic models, and, as with all predictive models, time will tell.
(M.G.) IVlajor-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. E.W. Petersdorf, J.A, Hanson, P.J. Martin, et al. N Engl J Med 345:1794-800, 2001. The development of DNA methods that allowed laboratories to determine high-resolution HLA typing based on nucleic acid differences has represented a fundamental advance of methodology for HLA typing. However, this development brought with it the problem of deciding how fine a resolution of HLA differences was enough for clinical use. Researchers advancing the HLA-typing field wondered whether fine differences detected using DNA-based typing techniques would be clinically meaningful. This article addresses that question in the context of hematopoietic stem ceil transplantation. The investigators used both classical serologic methods and DNA-based methods to type 471 patients and their unrelated bone marrow donors. Patients were undergoing transplantation for chronic myeloid leukemia. The chance of graft failure (expressed as the odd ratio) was determined for recipients of transplants from 4 groups: those with no detectable mismatches, those with a single class I DNA mismatch, those with a single class I serologic (antigen) mismatch, and those with 2 or more mismatches. They found that compared with recipient-donors pairs that had no mismatch, the presence of a single allelic DNA mismatch fared no worse, in contrast, compared with pairs having no mismatch, the presence of a single serologic (antigen) mismatch had more graft failure. Graft failure also increased in the presence of 2 or more mismatches.
CURRENT LITERATURE The authors concluded that serologic typing (antigen typing) and matching were clinically relevant for graft survival after marrow transplantation for patients with chronic myeloid leukemia. On the other hand, small HLA differences--detectable by DNA methods but not by serologic methods--appeared to result in outcomes no worse than those found among matched patients. Thus, serologic typing may represent a key level of resolution on which to base clinical decisions for donor-recipient matching. (S.D.)
Molecular defects underlying the Kell null phenotype. S. Leo, D.C.W. Russo, A.P. Roinor, ot a/. J Biol Chem 276:27281-27289, 2001. The Kell blood group system is highly polymorphic, consisting of over 20 antigens each associated with a single amino-acid substitution. Red blood cells (RBCs) with the K0 phenotype lack all these antigens because of the absence of the Kell glycoprotein. This article describes the molecular basis of 8 Ko people. Six probands were homozygous for either a premature stop codon (Arg128Stop [n 2]; Cys83Stop; Gin348Stop), a donor splice site mutation (g to a in intron 3), or a missense mutation in exon 18 leading to a Ser676Asn substitution. Two K0 probands were heterozygous for 2 mutations. One had 1 allele with a donor splice site mutation (g to a in intron 3) and the other allele with a missense mutation in exon 10 that resulted in a Ser363Asn substitution. The other heterozygous proband had 1 allele encoding the same Ser363Asn substitution in exon 10 and a premature stop codon in exon 6 (Arg192Stop) in the other allele. The Ser363Asn and Ser676Asn mutants, expressed in 293T cells, were retained in a pre-Golgi compartment and were not transported to the cell surface, indicating that these mutations inhibit trafficking. (M.E.R.)
Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1. J.M. Mou/ds, P.A. Zimmorman, D.K. Doumbo, ot a/. Blood 97:2879-2885, 2001. Antigens of the Knops blood group system are located on the complement receptor 1 (CRI). By using monoclonal antibody epitope mapping and serologic inhibition studies with CR1 deletion constructs, the authors were able to localize McC and SI a to the long homologous repeat D of CR1. This was also shown by Tamasaukas et al (Tamasauskas D, Powell V, Schawalder A, etal: Localization of Knops system antigens in the long homologous repeats [LHRs] of complement receptor 1. Transfusion 41: 1397-1404, 2001). Moulds, et al also report that single nucleotide polymorphisms in exon 29 of CR1 encode spgcific amino acid substitutions for the antithetical McCa/ McC u (Lys1590Glu) and Sla/Vil (Arg1601Gly) antigens. Identification of these mutations may provide insights into the role of v~iant forms of CR1 and Plasmodiumfalciparum invasion.
(M.E.R.) HIV transmissions From a window-period platelet donation. P.M. Kopko, L.P. Fornando, E.N. Bonnov, ot a/. Am J Clin Pathol 116:562-566, 2001. Screening of blood donors for the human immunodeficiency (HIV) p24 viral antigen was initiated in March 1996, with a predicted, decrease in the window period from approximately 40
(M.G.) IVlajor-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. E.W. Petersdorf, J.A, Hanson, P.J. Martin, et al. N Engl J Med 345:1794-800, 2001. The development of DNA methods that allowed laboratories to determine high-resolution HLA typing based on nucleic acid differences has represented a fundamental advance of methodology for HLA typing. However, this development brought with it the problem of deciding how fine a resolution of HLA differences was enough for clinical use. Researchers advancing the HLA-typing field wondered whether fine differences detected using DNA-based typing techniques would be clinically meaningful. This article addresses that question in the context of hematopoietic stem ceil transplantation. The investigators used both classical serologic methods and DNA-based methods to type 471 patients and their unrelated bone marrow donors. Patients were undergoing transplantation for chronic myeloid leukemia. The chance of graft failure (expressed as the odd ratio) was determined for recipients of transplants from 4 groups: those with no detectable mismatches, those with a single class I DNA mismatch, those with a single class I serologic (antigen) mismatch, and those with 2 or more mismatches. They found that compared with recipient-donors pairs that had no mismatch, the presence of a single allelic DNA mismatch fared no worse, in contrast, compared with pairs having no mismatch, the presence of a single serologic (antigen) mismatch had more graft failure. Graft failure also increased in the presence of 2 or more mismatches.
CURRENT LITERATURE The authors concluded that serologic typing (antigen typing) and matching were clinically relevant for graft survival after marrow transplantation for patients with chronic myeloid leukemia. On the other hand, small HLA differences--detectable by DNA methods but not by serologic methods--appeared to result in outcomes no worse than those found among matched patients. Thus, serologic typing may represent a key level of resolution on which to base clinical decisions for donor-recipient matching. (S.D.)
Molecular defects underlying the Kell null phenotype. S. Leo, D.C.W. Russo, A.P. Roinor, ot a/. J Biol Chem 276:27281-27289, 2001. The Kell blood group system is highly polymorphic, consisting of over 20 antigens each associated with a single amino-acid substitution. Red blood cells (RBCs) with the K0 phenotype lack all these antigens because of the absence of the Kell glycoprotein. This article describes the molecular basis of 8 Ko people. Six probands were homozygous for either a premature stop codon (Arg128Stop [n 2]; Cys83Stop; Gin348Stop), a donor splice site mutation (g to a in intron 3), or a missense mutation in exon 18 leading to a Ser676Asn substitution. Two K0 probands were heterozygous for 2 mutations. One had 1 allele with a donor splice site mutation (g to a in intron 3) and the other allele with a missense mutation in exon 10 that resulted in a Ser363Asn substitution. The other heterozygous proband had 1 allele encoding the same Ser363Asn substitution in exon 10 and a premature stop codon in exon 6 (Arg192Stop) in the other allele. The Ser363Asn and Ser676Asn mutants, expressed in 293T cells, were retained in a pre-Golgi compartment and were not transported to the cell surface, indicating that these mutations inhibit trafficking. (M.E.R.)
Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1. J.M. Mou/ds, P.A. Zimmorman, D.K. Doumbo, ot a/. Blood 97:2879-2885, 2001. Antigens of the Knops blood group system are located on the complement receptor 1 (CRI). By using monoclonal antibody epitope mapping and serologic inhibition studies with CR1 deletion constructs, the authors were able to localize McC and SI a to the long homologous repeat D of CR1. This was also shown by Tamasaukas et al (Tamasauskas D, Powell V, Schawalder A, etal: Localization of Knops system antigens in the long homologous repeats [LHRs] of complement receptor 1. Transfusion 41: 1397-1404, 2001). Moulds, et al also report that single nucleotide polymorphisms in exon 29 of CR1 encode spgcific amino acid substitutions for the antithetical McCa/ McC u (Lys1590Glu) and Sla/Vil (Arg1601Gly) antigens. Identification of these mutations may provide insights into the role of v~iant forms of CR1 and Plasmodiumfalciparum invasion.
(M.E.R.) HIV transmissions From a window-period platelet donation. P.M. Kopko, L.P. Fornando, E.N. Bonnov, ot a/. Am J Clin Pathol 116:562-566, 2001. Screening of blood donors for the human immunodeficiency (HIV) p24 viral antigen was initiated in March 1996, with a predicted, decrease in the window period from approximately 40