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PubMed1989

Mutations that change the immunological subtype of hepatitis B virus surface antigen and distinguish between antigenic and immunogenic determination.

The molecular basis of the d or y immunological subtype of hepatitis B virus (HBV) surface antigen (HBsAg) has been investigated by mutation of specific amino acid residues. When combined with substitution of serine 113 by threonine, replacement of arginine 122 by lysine or of tyrosine 134 by phenylalanine, or both of these changes, altered the antigenic subtype of HBsAg from y+d- to y+d+. These same mutations had a more dramatic effect on the subtype of antibodies induced by the antigens, a combination of all three mutations completely changing the subtype from y to d. Our study thus identifies residues in HBsAg that not only affect the subtype but discriminate between changes in antigenic and immunogenic behaviour. It also shows how the y and d subtypes may be manifest by the same molecule.

Amino Acid Sequence↗
PubMed2006

Prevalence of BK virus subtype I in Germany.

The primary infection with human polyomavirus BK (BKV) occurs in early childhood and leads to viral latency within the urogenital tract. Up to 90% of the adult population are seropositive. In immunosuppressed patients, the BKV may be reactivated resulting in typical disease patterns like hemorrhagic cystitis and tubulointerstitial nephritis. Based on serological and molecular methods, BKV isolates were classified into four subtypes previously. Sixty specimens obtained from German renal and bone marrow transplant recipients were analyzed to gain data on the prevalence of BKV subtypes in Germany. With 90.9%, BKV subtype I was found to be predominant in both patient groups. 6.1% of BKV strains were classified as subtype IV. This pattern of phylogenetic distribution is similar to that demonstrated previously in England, Tanzania, the United States and Japan. Remarkably, there was one German BKV virus with a sequence which clusters together with strain SB in subtype II. The BKV subtype I was found to consist of at least three subgroups designated as Ia, Ib, and Ic. While the majority of the German sequences represent subgroup Ic, most of the Japanese sequences are clearly distinct. These findings support the hypothesis of distinct geographical prevalence of BKV subgroups. For the genotyping region, a relationship of BKV subgroups to disease patterns like hemorrhagic cystitis or tubulointerstitial nephritis could not be demonstrated.

Amino Acid Sequence↗
PubMed2002

HHV-8 subtypes in South Africa: identification of a case suggesting a novel B variant.

Human herpesvirus 8 (HHV-8) has been identified as the causative agent for all forms of Kaposi's sarcoma and is also associated with the development of body cavity-based B-cell lymphomas and multicentric Castleman's disease. HHV-8 genomes are now classified into five major subtypes (A-E) that reflect sequence heterogeneity in the highly variable open reading frame (ORF) K1. To identify HHV-8 subtypes associated with different forms of Kaposi's sarcoma, we compared the ORF 26 and ORF-K1 gene sequences from South African patients with the prototype strains of the major subtypes, as well as published sequences from other African strains. DNA prepared from Kaposi's sarcoma biopsies and/or peripheral blood lymphocytes were available from 14 patients with postrenal transplant (iatrogenic) Kaposi's sarcoma, six patients with the African endemic form, and one patient with AIDS-related body cavity-based B-cell lymphoma. We identified a B2 subtype in six patients, four of whom also had a novel B5 type ORF 26 polymorphism. Two patients had B2 type patterns for both the ORF 26 and ORF-K1 genes. The ORF-K1 subtype A5 was identified in samples from three patients with a B3/C2 type polymorphism in the ORF 26 gene. A novel ORF-K1 B variant strain was identified in a patient with African endemic Kaposi's sarcoma, who also had a B3/C2 class ORF 26 pattern. In 58.3% of iatrogenic Kaposi's sarcoma patients, a B5-type ORF 26 gene sequence pattern was identified. No association was found among particular subtypes, geographical origin of patients, or clinical presentation.

Adult↗
PubMed2006

Comparative expressed sequence hybridization reveals differential gene expression in morphological breast cancer subtypes.

In this study, comparative expressed sequence hybridization (CESH) has been used to compare gene expression patterns in three morphologically different breast cancer subtypes: classic-type invasive lobular carcinoma (ILC), poorly differentiated ERBB2-negative invasive ductal carcinoma-not otherwise specified (IDC-NOS), and poorly differentiated ERBB2-positive IDC-NOS. CESH allows global detection of chromosomal regions with differential gene expression in a way similar to that of comparative genomic hybridization (CGH). Eight cases of each breast cancer subtype were included in the study. For each subtype, two pools of four cases each were constructed. CESH was used to compare both pools within the same morphological subtype, followed by a comparison of pools belonging to different subtypes. This revealed three chromosomal regions that were differentially expressed in ductal and lobular carcinomas, including relative overexpression at 8q13-q23 and 16q22, and relative underexpression at 8p21-p22. In addition, an expression signature characterized by relative overexpression at 3q24-q26.3, 14q23-31, 17q12, and 20q12-13 was identified for ERBB2-positive IDC-NOS. In summary, CESH analysis highlights chromosomal regions of differential gene expression that are associated with morphologically defined breast cancer subtypes and suggests that regions on chromosome 8 are of interest in the discrimination between ductal and lobular carcinomas. In addition, using CESH, it was possible to identify an ERBB2 expression signature, comprising four chromosomal regions with potential significance in the aggressive behaviour of ERBB2-positive IDC-NOS.

Breast Neoplasms↗
PubMedDate not supplied

Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis.

Nucleotide sequences from a total of 421 HEV isolates were retrieved from Genbank and analysed. Phylogenetically, HEV was classified into four major genotypes. Genotype 1 was more conserved and classified into five subtypes. The number of genotype 2 sequences was limited but can be classified into two subtypes. Genotypes 3 and 4 were extremely diverse and can be subdivided into ten and seven subtypes. Geographically, genotype 1 was isolated from tropical and several subtropical countries in Asia and Africa, and genotype 2 was from Mexico, Nigeria, and Chad; whereas genotype 3 was identified almost worldwide including Asia, Europe, Oceania, North and South America. In contrast, genotype 4 was found exclusively in Asia. It is speculated that genotype 3 originated in the western hemisphere and was imported to several Asian countries such as Japan, Korea and Taiwan, while genotype 4 has been indigenous and likely restricted to Asia. Genotypes 3 and 4 were not only identified in swine but also in wild animals such as boar and a deer. Furthermore, in most areas where genotypes 3 and 4 were characterised, sequences from both humans and animals were highly conserved, indicating they originated from the same infectious sources. Based upon nucleotide differences from five phylogenies, it is proposed that five, two, ten and seven subtypes for HEV genotypes 1, 2, 3 and 4 be designated alphabetised subtypes. Accordingly, a total of 24 subtypes (1a, 1b, 1c, 1d, 1e, 2a, 2b, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 4a, 4b, 4c, 4d, 4e, 4f and 4g) were given.

Animals↗
PubMed1992

Distribution of beta-adrenergic receptor subtypes in human post-mortem brain: alterations in limbic regions of schizophrenics.

The distribution of the beta 1 (beta 1) and beta 2 (beta 2) subtypes of the beta-adrenergic receptor was examined in rat and nondiseased control human tissue. The distribution of the beta 1 and beta 2 receptors was also examined in schizophrenic cases, with additional studies in schizophrenic suicide and nonschizophrenic suicide cases. Scatchard analysis of the binding of [125I]iodopindolol (IPIN) to cortical membranes showed a similar Kd in human (177 pM) and rat (161 pM), but a lower maximum binding site (Bmax) in the human tissue (18.7 fmol/mg protein and 55.6 fmol/mg protein). For the autoradiographic studies [125I]IPIN was used to visualize both subtypes (total) or was displaced with the selective beta 1-receptor antagonist ICI-89,406 to visualize beta 2 sites, or with the selective beta 2-receptor antagonist ICI-118,551 to visualize beta 1 sites. Important differences in the regional distribution of the two subtypes of the beta-adrenergic receptors were noted between rat and human. In the nucleus accumbens and ventral putamen (ventral striatum), a patchy distribution of beta 1 receptors was observed that was not evident in the rat. These patches were aligned with markers of the matrix compartment of the striatum. The schizophrenic cases showed significant increases in the labeling of the beta 1-receptor patches with [125I]IPIN. In contrast to the frontal cortex of the nondisease controls, the parietal and temporal cortex showed a high ratio of beta 1 to beta 2 receptors and a highly laminar organization of the subtypes. [125I]IPIN binding to beta 1 receptors was highest in the external laminae with the reverse gradient for the beta 2 subtype. The medial temporal cortex displayed an alteration in the ratio of the 2 subtypes of the beta-adrenergic receptor, with the parahippocampus and hippocampus of the human, in contrast to the rat brain, predominantly expressing the beta 2 receptor. Moreover, there were consistently higher densities of beta 2 receptors in the hippocampus of the right hemisphere than the left hemisphere of the nondisease controls. There was not a left and right hemispheric asymmetry of beta 2 receptors in the hippocampus of elderly schizophrenics or in young schizophrenics who committed suicide. The asymmetry was evident in nonschizophrenic suicides, suggesting that the lack of asymmetry in the hippocampus of schizophrenics is evident early in the disease process. Thus limbic structures show alterations in the patterning of beta 1 and beta 2 receptors in the schizophrenic cases.

Adult↗
PubMed1993

Identification of a fourth angiotensin AT1 receptor subtype in rat.

Angiotensin II is a major regulator of cardiovascular function, fluid homeostasis and also plays a role in long-term cardiovascular disease processes. At present it is unclear if and how the diverse functions of angiotensin II may relate to different cellular receptors for this vasoactive peptide. In order to identify subtypes of angiotensin receptors we used a PCR-mediated cloning approach. Oligonucleotide sequences for PCR amplification of angiotensin receptors were selected on the basis of nucleotide sequences conserved between species. Since the coding regions of AT1-type receptors appear to be located on a single exon, we used genomic DNA as a template in the PCR reactions. Resulting amplification products represented a mixture of four different sequences as assessed by T-tracking and sequencing of the partial clones. Three of the clones encode for sequences already known, whereas the fourth clone encoded a novel receptor subtype which we have termed AT1C. Deduced amino acid sequences of the four different receptor subtypes are highly homologous. The AT1C receptor nucleotide sequence homology was greatest to the described AT3 receptor (95%) and less so to the published AT1A (90%) and AT1B (82%) receptor subtypes. The variety and tissue- specific expression of AT1 receptor subtypes and coexpression of different receptor subtypes may account for the diverse tissue- specific actions of angiotensin.

Amino Acid Sequence↗
PubMed1994

Different sensitivity of alpha 2A-C10 and alpha 2C-C4 receptor subtypes in coupling to inhibition of cAMP accumulation.

Two human alpha 2-adrenergic receptor subtypes, alpha 2A-C10 and alpha 2C-C4, were compared with respect to their ability to inhibit stimulated cAMP-production. The inhibition was transduced with about one order of magnitude higher sensitivity in the alpha 2C-C4 subtype than in the alpha 2A-C10 subtype. The phorbol ester, TPA, known to desensitize alpha 2-adrenergic receptor function, possible through phosphorylation of Gi, almost completely abolished the inhibition of cAMP-production in the alpha 2C-C4 subtype, while only a partial effect was seen in the alpha 2A-C10 subtype. These results suggest that the receptor subtypes differ with respect to their coupling efficiency to adenylyl cyclase.

Adenine↗
PubMed2000

HPV subtype analysis in lower genital tract neoplasms of female renal transplant recipients.

OBJECTIVE: Immunocompromised patients, such as female renal transplant recipients, have an increased incidence of neoplasms involving the lower genital tract (i.e., cervix, vagina, vulva). The relationship between lower genital tract neoplasms and human papillomavirus (HPV) infection has been established and high-risk oncogenic subtypes have been identified (HPV 16, 18, 45, and 56). The purpose of this study is to evaluate HPV subtypes present in lower genital tract neoplasms of post renal transplant women and compare HPV subtypes found in these patients with immunocompetent patients having similar neoplasms and normal immunocompetent controls. METHODS: Twenty specimens from lower genital tract neoplasms of 16 renal transplant patients, 13 specimens from 13 immunocompetent patients with similar histology, and 13 patients with normal lower genital tract histology were analyzed for the presence of HPV using polymerase chain reaction. HPV primers including the L1 (late) region consensus primers and primers specific for the HPV E6 (early) region for subtypes 6, 11, 16, and 18 were amplified with DNA from the above patient samples. RESULTS: Overall, HPV was detected in 21/46 specimens tested. Thirteen of the HPV-positive specimens were from transplant patients, and 8 were from immunocompetent patients (5 immunocompetent with disease and 3 normal patients). This difference in the total number of HPV-positive cases was statistically significant between the transplant and immunocompetent group (P = 0.02). Although no difference in HPV 6 and/or 11 was detected between the two groups, HPV subtypes 16 and/or 18 approached statistical significant difference (P = 0.06). CONCLUSIONS: High-risk oncogenic HPV subtypes 16 and/or 18 were found at a higher rate in transplant patients compared with their immunocompetent counterparts. The combination of immunocompromise and increased HPV 16 and/or 18 positivity may place these patients at increased risk for aggressive lower genital tract neoplastic progression.

DNA, Viral↗
PubMed1996

Balloon angioplasty significantly increases collagen content but does not alter collagen subtype I/III ratios in the atherosclerotic rabbit iliac model.

Angioplasty has been reported to increase collagen content and to alter vascular collagen alpha 1(I), alpha 2(I), and alpha 1(III) mRNA levels. Collagen synthesis is tightly regulated by complex translational and post-translational mechanisms such that mRNA levels may not necessarily reflect biosynthesis. To test whether collagen subtype I and III protein levels are altered by angioplasty, we quantitatively analysed collagen I/III protein ratios at 4 weeks after balloon angioplasty. Twenty New Zealand White rabbits underwent iliac artery balloon de-endothelialization and then were placed on a 0.5% cholesterol/6% peanut oil diet for 7 weeks at which time angioplasty was performed on arteries with > or = 50% stenosis. Arteries with < 50% stenosis were not dilated and served as controls. Animals were killed 4 weeks later and hydroxyproline (OH-pro) content and subtype I/III ratios were analysed in 5-mm mid-iliac sections. OH-pro was measured by a colorimetric assay. Subtype ratios were determined by a highly quantitative two-dimensional cyanogen bromide peptide mapping method. The degree of stenosis was measured as the minimal vessel lumen diameter and calculated as a percentage stenosis compared to a proximal reference segment. Calculated collagen content (micrograms/mg tissue) was significantly higher 4 weeks following angioplasty compared to the non-dilated group (220.4 +/- 70.8 v 308.2 +/- 26.9, P = 0.04; n = 12), despite similar percentage stenosis in the primary and restenotic lesions. The ratio of collagen I/III subtype protein distribution was not significantly different in the non-dilated and angioplastied groups (4.88 +/- 1.00 v 4.70 +/- 0.82, respectively). These studies are the first to provide data on collagen I/III subtypes following angioplasty and suggest that collagen accumulation may be more important in restenosis than alteration of collagen protein subtypes.

Angioplasty, Balloon↗
PubMed2002

Alpha(1)-adrenoceptor subtypes mediate negative inotropy in myocardium from alpha(1A/C)-knockout and wild type mice.

Cardiac alpha(1)-adrenoceptors (AR) have two predominant subtypes (alpha(1A)-AR and alpha(1B)-AR) however, their roles in regulating contraction are unclear. We determined the effects of stimulating alpha(1A)-AR (using the subtype-selective agonist A61603) and alpha(1B)-AR (using a gene knockout mouse lacking alpha(1A)-AR) separately, and together (using phenylephrine) on Ca(2+) transients, intracellular pH, and contraction of mouse cardiac trabeculae. Stimulation of alpha(1)-AR subtypes separately or together caused a triphasic contractile response. After a transient ( approximately 3%) force rise (phase 1), force declined markedly (phase 2), then partially recovered (phase 3). In phase 2, the force decline (% of initial) with combined alpha(1A)-AR plus alpha(1B)-AR stimulation (50+/-3%) was more than with separate subtype stimulation (P<0.01), suggesting alpha(1A)-AR and alpha(1B)-AR mediate additive effects during phase 2. Force decline in phase 2 paralleled decreases of Ca(2+) transients that were reduced more with combined vs. separate subtype stimulation. During phase 3 the final force reduction was similar with stimulation of alpha(1A)-AR (20+/-5%), or alpha(1B)-AR (20+/-3%), or both (26+/-4%) suggesting alpha(1A)-AR and alpha(1B)-AR mediate non-additive effects during phase 3. In contrast, Ca(2+) transients recovered fully in phase 3 suggesting reduced force in phase 3 involved decreased myofilament Ca(2+)-sensitivity. Decreased Ca(2+)-sensitivity was not mediated by changes of intracellular pH since this was not affected by alpha(1)-AR stimulation. In contrast to mouse trabeculae, rat trabeculae demonstrated a positive inotropic response to alpha(1)-AR stimulation. In conclusion, for mouse myocardium in vitro both alpha(1)-adrenoceptor subtypes mediate negative inotropy involving decreased Ca(2+) transients and a decreased Ca(2+) sensitivity that does not involve altered intracellular pH.

Animals↗
PubMed1998

Distribution of muscarinic receptor subtypes in rat small intestine.

Despite its great promise, small intestinal transplantation in some patients is complicated by difficult postoperative management. The reasons for this are complex. In a rat model of small intestinal transplantation, frequencies of migrating myoelectric complexes during fasting are reduced in ileal isografts and muscarinic receptor density is decreased. We hypothesized that the distribution of muscarinic 1 receptors localized to enteric neurons is altered after small intestinal transplantation. Distal small intestine was orthotopically transplanted in Lewis-to-Lewis donor-recipient combinations. At 3 months, transplanted and normal ileum was obtained to prepare membrane fractions. [N-methyl-3H]Scopolamine served as ligand, while scopolamine methylbromide, pirenzepine, and methoctramine were used in competitive homologous and heterologous displacement experiments. Receptor subtype models were examined by nonlinear regression analysis. In normal and transplanted ileum, heterologous displacement was consistent with three site models (P < 0.05). In normals, the muscarinic 1 receptor subtype was most abundant, with a relative distribution of 69 to 78%. There was a relative distribution of 13 to 16% for muscarinic 3 receptor subtype. After transplantation, the muscarinic 1 subtype decreased to a mean of 45% but the muscarinic 3 subtype increased to a mean of 42%. Using pirenzepine, mean pKD values were not different between the two groups. It is concluded that the decrease in muscarinic 1 receptor subtype after transplantation could be related to neuronal cell loss or to downregulation of the expression of muscarinic 1 receptors. The results did not support defective posttranslational processing of receptor proteins.

Animals↗
PubMed1999

Molecular characterization of human immunodeficiency virus (HIV)-1 and -2 in individuals from guinea-bissau with single or dual infections: predominance of a distinct HIV-1 subtype A/G recombinant in West Africa.

Guinea-Bissau in West Africa has the highest prevalence of human immunodeficiency virus (HIV)-2 infection in the world, but recently the HIV-1 prevalence increased rapidly with the subsequent appearance of HIV-1 and HIV-2 dual infections. Information about the genetic subtypes of HIV in the region is limited. Therefore, we characterized the env V3 region of HIV-1 and HIV-2 variants through direct DNA sequencing of peripheral blood mononuclear cell samples from 18 individuals with HIV-1 only and 9 individuals with dual infection. Phylogenetic analyses of these new sequences and database sequences from other West African countries showed that all HIV-1 and HIV-2 sequences from singly as well as dually infected individuals, except one, clustered among HIV-1 subtype A and HIV-2 subtype A, respectively. Importantly, a majority of the HIV-1 sequences from Guinea-Bissau and neighbouring countries were closely related with the isolates IbNG, DJ263, and DJ264, which share a common subtype A/G recombination pattern. Analysis of pol gene sequences from selected HIV-1 variants showed that "IbNG-like" viruses in Guinea-Bissau are also recombinant, indicating that the HIV-1 epidemic in Guinea-Bissau and neighbouring countries is dominated by an epidemic spread of a distinct subtype A/G recombinant, which is strikingly similar to the epidemic spread of a subtype A/E recombinant in Southeast Asia. Furthermore, the HIV-1 and HIV-2 variants carried by individuals with dual infection were intermixed with variants from singly infected individuals, indicating that variants involved in dual and single infections have common epidemiological histories.

Adult↗
PubMed2001

Human T-lymphotropic virus type II RFLP subtypes a0 and b4/b5 are associated with different demographic and geographic characteristics in the United States.

Human T-lymphotropic virus type II (HTLV-II) prevalence is very low among the general U.S. population, intermediate among American Indians, and high among injecting drug users and their sexual partners. However, the transmission dynamics underlying this distribution are not well described. We obtained blood specimens from 493 blood donors found to be seropositive for HTLV-II at blood centers in five U.S. cities. Nested polymerase chain reaction was used to amplify a 672-bp region of the HTLV-II long terminal repeat region, and restriction fragment length polymorphism (RFLP) analysis was performed to classify each virus into subtypes as defined by Switzer et al. (1995, J. Virol. 69, 621-632). Associations between RFLP subtype and other characteristics were analyzed using multivariable logistic regression. HTLV-II subtype a0 was independently associated with age over 30 years (odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.13-3.99) and with Black race/ethnicity (OR = 2.00, 95% CI 1.10-3.65 versus Hispanic race/ethnicity). Conversely, HTLV-II RFLP subtypes b4 and b5 were significantly more common among American Indian (OR = 3.77, 95% CI 1.23-11.57) and Other race/ethnicity (OR = 4.22, 95% CI 1.25-14.27, both versus Black race/ethnicity) and at the Oklahoma City blood center (OR = 3.57, 95% CI 1.08-11.84 compared to Washington, DC/Baltimore). There may have been at least two transmission foci of HTLV-II in the United States: a modest HTLV-II subtype a0 epidemic of unknown source in the 1960s and 1970s spread predominantly among Black persons in several geographic areas and a smaller focus of HTLV-II subtypes b4/b5 among non-Black individuals in Oklahoma and perhaps in other areas not examined by this study.

Adolescent↗
PubMedDate not supplied

Differences in ligand binding profiles between cloned rabbit and human 5-HT1D alpha and 5-HT1D beta receptors: ketanserin and methiothepin distinguish rabbit 5-HT1D receptor subtypes.

The study of serotonin receptor function has been complicated by the extreme molecular diversity of serotonin receptor subtypes, the lack of selective agonists and antagonists for many of the subtypes, and divergence in the pharmacological properties of a single receptor subtype across different animal species. An example of this pharmacological diversity between species homologues is provided by the 5-HT1D receptor subfamily. To further advance the ability to characterize and pharmacologically compare functional responses mediated by native 5-HT1D receptors, we have cloned the 5-HT1D alpha and 5-HT1D beta receptor subtypes from the rabbit and evaluated their pharmacological profiles using radioligand binding assays. The deduced amino acid sequences of the rabbit 5-HT1D alpha and 5-HT1D beta receptor genes displayed 60% overall identity [75% transmembrane (TM) identity] to each other and > 90% overall identity (95% TM identity) to their corresponding human homologues. Two compounds were identified in binding assays which discriminated between the closely-related 5-HT1D receptors. Ketanserin exhibited high affinity (pKi = 7.66) and selectivity (> 20-fold) for the 5-HT1D alpha receptor while methiothepin displayed high affinity (pKi = 7.86) and selectivity (16-fold) for the 5-HT1D beta receptor subtype. The rabbit and human recombinant 5-HT1D receptors showed significant intraspecies (rabbit 5-HT1D alpha vs. 5-HT1D beta) and interspecies (i.e. rabbit vs. human 5-HT1D alpha) similarities in their ligand binding profiles. These data suggest that 5-HT1D-mediated responses in rabbit preparations may provide information relevant to the pharmacology of the 5-HT1D receptor subtypes in humans.

Amino Acid Sequence↗
PubMed1991

Structure of the HLA-A*0204 antigen, found in South American Indians. Spatial clustering of HLA-A2 subtype polymorphism.

The primary structure of the HLA-A2 subtype A*0204 (isoelectric focusing variant A2.4) has been determined. cDNA encoding this subtype was amplified by the polymerase chain reaction. Four independent full-length cDNA clones encoding A*0204 were analyzed to obtain a consensus sequence for this subtype. A*0204 differs from A*0201 by a single nucleotide change of G to T through the coding regions, resulting in an Arg to Met change at position 97. This substitution accounts for the isoelectric focusing pattern of the subtype. The same change occurs in other HLA-A specificities in association with other changes in its vicinity. The absence of additional substitutions in A*0204 suggests that it could have arisen from A*0201 by point mutation, and that recurrent mutations may take place during HLA diversification. The spatial location of this change implies that A*0204 must be a functional variant. Comparison of its sequence with other HLA-A2 subtypes reveals that much of the HLA-A2 subtype polymorphism is generated by variations in four neighboring positions, including position 97, which are located in two adjacent beta-strands on the floor of the peptide binding site of the molecule.

Amino Acid Sequence↗
PubMed1983

Definition of four HLA-A2 subtypes by CML typing and biochemical analysis.

The population of HLA-A2-positive individuals, currently considered serologically homogeneous, can be divided into three subtypes on the basis of antigen recognition by various HLA-A2-specific cytotoxic T lymphocytes (CTLs). When these three types of HLA-A2 antigens were analyzed biochemically, they were found to be distinct. Isoelectric focusing (IEF) of HLA antigens digested with neuraminidase (NANAse) suggested that the difference(s) reside in the polypeptide backbone of the HLA-A2 heavy chain. Biochemical analysis distinguishes three distinct categories of HLA-A2 antigens: (1) a major subtype, designated HLA-A2.I, (2) a minor subtype, designated HLA-A2.II, possessing a more basic isoelectric point (IEP) and (3) a minor HLA-A2 subtype more acidic in its IEP than HLA-A2.I, designated HLA-A2.III. A fourth HLA-A2 subtype could be defined by discordance between cell-mediated lympholysis (CML) typing and biochemical analysis. The latter HLA-A2 antigen was defined as a variant by CTL, but was biochemically indistinguishable from the major subtype HLA-A2.I.

Electrophoresis, Polyacrylamide Gel↗
PubMed1996

Subtype 2 and atypical angiotensin receptors in the human heart.

Angiotensin receptors have been described in the human heart and are suspected to play a central role in remodeling after myocardial infarction and in cardiac hypertrophy. Two subtypes, AT1 and AT2, have so far been described in humans, with AT2 being the dominant subtype in human atria. We have now determined subtype numbers and distribution by binding in ventricular myocardium from patients with end-stage heart failure. We found about 50-80% of subtype AT2 in the right and left ventricles from patients with end-stage heart failure due to coronary artery disease and cardiomyopathy, indicating that AT2 is the dominant angiotensin receptor subtype in the whole human heart. To determine the cellular localization of angiotensin receptors in human myocardium in addition to the known localization on myocytes, smooth muscle cells and endothelial cells, we investigated cardiac fibroblasts. They express an angiotensin receptor with yet incompletely understood binding characteristics which is coupled to proliferation and DNA synthesis. As AT2 is the dominant angiotensin receptor subtype in human heart, we cloned the complete mRNA sequence by a rapid amplification of cDNA ends (RACE) procedure and thereafter the promoter sequence from a human genomic library. Once the sequence of the mRNA and thus exon 1 was obtained by the RACE-PCR, a probe was constructed for the most 5' region of exon 1 and used for screening of a human genomic DNA bank. After cutting of the positive clones with EcoR1 and Not1, a 4000 bp fragment hybridized with the probe and was further sequenced. A functional AT2 promoter, with > 90% homology with the mouse promoter and 35% homology with the human AT1 promoter containing numerous cis-acting sequences for basal (TFIID) and inducible (AP-1, PEA-3, CBF) transcription factors in the first 1000 bp was identified.

DNA↗