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BACKGROUND: Functional somatic symptoms (FFS) and bodily distress disorders are highly prevalent across all medical settings. Services for these patients are dispersed across the health care system with minimal conceptual and operational integration, and patients do not currently access therapeutic offers in significant numbers due to a mismatch between their and professionals' understanding of the nature of the symptoms. New service models are urgently needed to address patients' needs and to align with advances in aetiological evidence and diagnostic classification systems to overcome the body-mind dichotomy. METHOD: A panel of clinical experts from different clinical services involved in providing aspects of health care for patients with functional symptoms reviewed the current care provision. This review and the results from a focus group exploration of patients with lived experience of functional symptoms were explored by the multidisciplinary expert group, and the conclusions are summarised as recommendations for best practice. RESULTS: The mapping exercise and multidisciplinary expert consultation revealed five themes for service improvement and pathway development: time/access, communication, barrier-free care, choice and governance. Service users identified four meta-themes for best practice recommendations: focus on healthcare professional communication and listening skills as well as professional attributes and knowledge base to help patients being both believed and understood in order to accept their condition; systemic and care pathway issues such as stronger emphasis on primary care as the first point of contact for patients, resources to reduce the length of the patient journey from initial assessment to diagnosis and treatment. CONCLUSION: We propose a novel, integrated care pathway for patients with 'functional somatic disorder', which delivers care according to and working with patients' explanatory beliefs. The therapeutic model should operate based upon an understanding of the embodied nature of patient's complaints and provide flexible access points to the care pathway.
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Prestação Integrada de Cuidados de Saúde , Sintomas Inexplicáveis , Transtornos Somatoformes , Humanos , Prestação Integrada de Cuidados de Saúde/organização & administração , Transtornos Somatoformes/terapia , Transtornos Somatoformes/diagnóstico , Grupos Focais , Participação dos Interessados , FemininoAssuntos
Mudança Climática , Combustíveis Fósseis , Humanos , Saúde Global , Política de Saúde , Relatório de PesquisaRESUMO
Cord blood stem cells are an attractive starting source for the production of red blood cells in vitro for therapy because of additional expansion potential compared with adult peripheral blood progenitors and cord blood banks usually being more representative of national populations than blood donors. Consequently, it is important to establish how similar cord RBCs are to adult cells. In this study, we used multiplex tandem mass tag labeling combined with nano-LC-MS/MS to compare the proteome of adult and cord RBCs and reticulocytes. 2838 unique proteins were identified, providing the most comprehensive compendium of RBC proteins to date. Using stringent criteria, 1674 proteins were quantified, and only a small number differed in amount between adult and cord RBC. We focused on proteins critical for RBC function. Of these, only the expected differences in globin subunits, along with higher levels of carbonic anhydrase 1 and 2 and aquaporin-1 in adult RBCs would be expected to have a phenotypic effect since they are associated with the differences in gaseous exchange between adults and neonates. Since the RBC and reticulocyte samples used were autologous, we catalogue the change in proteome following reticulocyte maturation. The majority of proteins (>60% of the 1671 quantified) reduced in abundance between 2- and 100-fold following maturation. However, â¼5% were at a higher level in RBCs, localized almost exclusively to cell membranes, in keeping with the known clearance of intracellular recycling pools during reticulocyte maturation. Overall, these data suggest that, with respect to the proteome, there is no barrier to the use of cord progenitors for the in vitro generation of RBCs for transfusion to adults other than the expression of fetal, not adult, hemoglobin.
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Células Eritroides/citologia , Sangue Fetal/citologia , Proteoma/análise , Proteômica/métodos , Reticulócitos/citologia , Adulto , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Diferenciação Celular , Cromatografia Líquida , Células Eritroides/metabolismo , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Reticulócitos/metabolismo , Espectrometria de Massas em TandemRESUMO
Comparison of normal erythroblasts and erythroblasts from persons with the rare In(Lu) type of Lu(a-b-) blood group phenotype showed increased transcription levels for 314 genes and reduced levels for 354 genes in In(Lu) cells. Many erythroid-specific genes (including ALAS2, SLC4A1) had reduced transcript levels, suggesting the phenotype resulted from a transcription factor abnormality. A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. In all cases the mutant EKLF allele occurred in the presence of a normal EKLF allele. Nine different loss-of-function mutations were identified. One mutation abolished a GATA1 binding site in the EKLF promoter (-124T>C). Two mutations (Leu127X; Lys292X) resulted in premature termination codons, 2 (Pro190LeufsX47; Arg319GlufsX34) in frameshifts, and 4 in amino acid substitution of conserved residues in zinc finger domain 1 (His299Tyr) or domain 2 (Arg328Leu; Arg328His; Arg331Gly). Persons with the In(Lu) phenotype have no reported pathology, indicating that one functional EKLF allele is sufficient to sustain human erythropoiesis. These data provide the first description of inactivating mutations in human EKLF and the first demonstration of a blood group phenotype resulting from mutations in a transcription factor.
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Moléculas de Adesão Celular/genética , Fatores de Transcrição Kruppel-Like/genética , Sistema do Grupo Sanguíneo Lutheran/genética , Mutação , Proteínas de Neoplasias/genética , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Primers do DNA/genética , DNA Complementar/genética , Eritroblastos/metabolismo , Perfilação da Expressão Gênica , Genótipo , Humanos , Fatores de Transcrição Kruppel-Like/química , Modelos Moleculares , Dados de Sequência Molecular , Fenótipo , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Dedos de Zinco/genéticaRESUMO
Long-term global scenarios have underpinned research and assessment of global environmental change for four decades. Over the past ten years, the climate change research community has developed a scenario framework combining alternative futures of climate and society to facilitate integrated research and consistent assessment to inform policy. Here we assess how well this framework is working and what challenges it faces. We synthesize insights from scenario-based literature, community discussions and recent experience in assessments, concluding that the framework has been widely adopted across research communities and is largely meeting immediate needs. However, some mixed successes and a changing policy and research landscape present key challenges, and we recommend several new directions for the development and use of this framework.
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The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.
Assuntos
Antígenos de Grupos Sanguíneos/genética , Proliferação de Células , Células Eritroides/citologia , Glicoproteínas de Membrana/genética , Antígenos de Grupos Sanguíneos/química , Antígenos de Grupos Sanguíneos/metabolismo , Plaquetas/metabolismo , Células Cultivadas , Membrana Eritrocítica/metabolismo , Células Eritroides/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Mutação , Fenótipo , Ligação Proteica , Sequenciamento do ExomaRESUMO
INTRODUCTION: Goal-setting is recommended for patients with multimorbidity, but there is little evidence to support its use in general practice. OBJECTIVE: To assess the feasibility of goal-setting for patients with multimorbidity, before undertaking a definitive trial. DESIGN AND SETTING: Cluster-randomised controlled feasibility trial of goal-setting compared with control in six general practices. PARTICIPANTS: Adults with two or more long term health conditions and at risk of unplanned hospital admission. INTERVENTIONS: General practitioners (GPs) underwent training and patients were asked to consider goals before an initial goal-setting consultation and a follow-up consultation 6 months later. The control group received usual care planning. OUTCOME MEASURES: Health-related quality of life (EQ-5D-5L), capability (ICEpop CAPability measure for Older people), Patient Assessment of Chronic Illness Care and healthcare use. All consultations were video-recorded or audio-recorded, and focus groups were held with participating GPs and patients. RESULTS: Fifty-two participants were recruited with a response rate of 12%. Full follow-up data were available for 41. In the goal-setting group, mean age was 80.4 years, 54% were female and the median number of prescribed medications was 13, compared with 77.2 years, 39% female and 11.5 medications in the control group. The mean initial consultation time was 23.0 min in the goal-setting group and 19.2 in the control group. Overall 28% of patient participants had no cognitive impairment. Participants set between one and three goals on a wide range of subjects, such as chronic disease management, walking, maintaining social and leisure interests, and weight management. Patient participants found goal-setting acceptable and would have liked more frequent follow-up. GPs unanimously liked goal-setting and felt it delivered more patient-centred care, and they highlighted the importance of training. CONCLUSIONS: This goal-setting intervention was feasible to deliver in general practice. A larger, definitive study is needed to test its effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN13248305; Post-results.
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Objetivos , Multimorbidade , Pacientes/psicologia , Atenção Primária à Saúde , Melhoria de Qualidade , Adulto , Estudos de Viabilidade , Feminino , Grupos Focais , Humanos , Masculino , Relações Médico-Paciente , Qualidade de Vida , Encaminhamento e Consulta , Reino UnidoRESUMO
Tn polyagglutination results from inactivating mutations in C1GALT1C1, an X-borne gene encoding a core 1 beta3-galactosyltransferase-specific molecular chaperone (cosmc) required for the functioning of T-synthase (beta 1,3-galactosyltransferase), a glycosyltransferase essential for the correct biosynthesis of O-glycans. This study found novel inactivating mutations (Glu152Lys, Ser193Pro and Met1Ile) in the coding sequence of C1GALT1C1 in three Tn positive individuals and a complete lack of C1GALT1C1 cDNA expression was observed in an additional Tn positive individual. In addition, expression of ST6GALNAC1, which encodes (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1, 3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 and gives rise to sialyl-Tn antigen, was present at comparable levels in normal and Tn-positive human erythroblasts. Expression studies of wild-type and Tn positive C1GALT1C1 cDNA in the Jurkat cell line confirmed that the amino acid substitutions observed in Tn are inactivating. Analysis of the transcriptome of cultured normal and Tn positive erythroblasts revealed numerous differences in gene expression. Reduced transcript levels for fatty acid binding protein 5 (FABP5) and plexin D1 (PLXND1), and increased levels for aquaporin 3 (AQP3) were confirmed by quantitative real-time polymerase chain reaction. These data show that alteration of O-glycan structures resulting from T-synthase deficiency is accompanied by altered expression of a wide variety of genes in erythroid cells.
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Antígenos Glicosídicos Associados a Tumores/genética , Galactosiltransferases/genética , Hemaglutinação/genética , Chaperonas Moleculares/genética , Mutação/genética , Células Sanguíneas/metabolismo , Eritroblastos/metabolismo , Galactosiltransferases/metabolismo , Humanos , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: The glycophorin (GP) molecule associated with the GP.Dane phenotype is a GP(A-B-A) hybrid that contains some amino acids encoded by the Pseudoexon 3 of GYPB and Asn(45) of GPA and carries the low-prevalence MNS antigens DANE and Mur. Serum from a woman of English ancestry contained an immunoglobulin M alloantibody to a high-prevalence MNS antigen, and the purpose of this study was to identify the molecular basis of her phenotype. STUDY DESIGN AND METHODS: Hemagglutination, Western blotting, and DNA analyses were performed by standard methods. RESULTS: Tests of the proband's RBCs with monoclonal antibodies indicated a change of amino acids between positions 27 and 55 of GPA. Her RBCs expressed M, s, Mur, and DANE antigens and were M(g)-negative. The antigen recognized by her antibody was sensitive to treatment with papain, ficin, and trypsin and resistant to alpha-chymotrypsin and dithiothreitol. Sequencing of DNA from the proband revealed a sequence of nucleotides identical to the GYP(A-B-A) encoding GP.Dane but without the adenyl nucleotide substitution, which has been predicted to change Ile(46) of GPA to Asn(45). Testing of her immediate family revealed the presence of an M(k) gene. CONCLUSION: The proband had a novel GYP(A-B-A) encoding a DANE+ GP that is in cis to GYPB(s) and in trans to M(k). The high-prevalence antigen lacking from this GP.Dane phenotype and recognized by the proband's serum is called ENDA (ISBT Number MNS44). Our results indicate that the change of Ile(46) of GPA to Asn(45) of GP.Dane is not required for expression of the DANE antigen.
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Anticorpos/imunologia , Antígenos de Grupos Sanguíneos/imunologia , Glicoforinas/imunologia , Sequência de Aminoácidos , Antígenos de Grupos Sanguíneos/genética , Éxons/genética , Feminino , Glicoforinas/química , Glicoforinas/genética , Hemaglutinação/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Análise de SequênciaRESUMO
BACKGROUND: The null phenotype of the Lutheran blood group system, Lu(null) or Lu(a-b-), is characterized by the lack of all Lutheran system antigens. It can arise from three genetic backgrounds: recessive, dominant, or X-linked. Lu(null) of the recessive type appears to result from homozygosity for an inactive LU gene. STUDY DESIGN AND METHODS: Three unrelated recessive Lu(null) individuals were assessed by standard serologic tests. All exons of the LU gene were directly sequenced from amplified genomic DNA. The validity of the observed mutations within the LU gene was confirmed by the use of either restriction enzymes or allele-specific primers. RESULTS: All three individuals had the serologic characteristics of recessive Lu(null). One individual was doubly heterozygous for a nonsense mutation 691C>T in exon 6 (Arg231STOP) and a deletion of LU exons 3 and 4. The other two samples showed homozygous nonsense mutations: one had 711C>A in exon 6 (Cys237STOP) and the other 361C>T in exon 3 (Arg121STOP). CONCLUSIONS: The results revealed four unique genetic backgrounds from three examples of the rare recessive Lu(null) phenotype, each encoding Lutheran glycoproteins with a disrupted structure.
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Moléculas de Adesão Celular/genética , Sistema do Grupo Sanguíneo Lutheran , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Sequência de Bases , Análise Mutacional de DNA , Feminino , Genes Recessivos , Humanos , Sistema do Grupo Sanguíneo Lutheran/genética , Masculino , Testes SorológicosRESUMO
BACKGROUND: The KEL2/KEL1 (k/K) blood group polymorphism represents 578C>T in the KEL gene and Thr193Met in the Kell glycoprotein. Anti-KEL1 can cause severe hemolytic disease of the fetus and newborn. Molecular genotyping for KEL*1 is routinely used for assessing whether a fetus is at risk. Red blood cells (RBCs) from a KEL:1 blood donor (D1) were found to have abnormal KEL1 expression during evaluation of anti-KEL1 reagents. STUDY DESIGN AND METHODS: Kell genotyping methods, including KEL exon 6 direct sequencing, were applied. KEL cDNA from D1 was sequenced. Flow cytometry was used to assess KEL1 and KEL2 RBC expression. RESULTS: RBCs from the donor, her mother, and an unrelated donor gave weak or negative reactions with some anti-KEL1 reagents. Other Kell-system antigens appeared normal. The three individuals were homozygous for KEL C578 (KEL*2) but heterozygous for a 577A>T transversion, encoding Ser193. They appeared to be KEL*2 homozygotes by routine genotyping methods. Flow cytometry revealed weak KEL1 expression and normal KEL2, similar to that of KEL*2 homozygotes. CONCLUSION: Ser193 in the Kell glycoprotein appears to result in expression of abnormal KEL1, in addition to KEL2. The mutation is not detected by routine Kell genotyping methods and, because of unpredicted KEL1 expression, could lead to a misdiagnosis.
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Sequência de Bases/genética , Expressão Gênica , Glicoproteínas/genética , Sistema do Grupo Sanguíneo de Kell/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Adulto , Doadores de Sangue , Análise Mutacional de DNA/métodos , DNA Complementar/genética , Eritroblastose Fetal/genética , Éxons/genética , Feminino , Doenças Fetais/genética , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , MasculinoRESUMO
BACKGROUND: The JAHK antigen was first described in 1995 as a low-frequency red blood cell antigen. Family studies confirmed the association of the antigen with the rare r(G) phenotype of the Rh blood group system, which is associated with weak expression of C and e, but normal G expression. JAHK was allocated the Rh number RH53. The serologic findings indicated the location of the antigen on the RhCE protein, although the molecular basis for JAHK has not been known. STUDY DESIGN AND METHODS: The RHCE gene of eight persons from three unrelated families was analyzed by exon amplification and direct sequencing. Four of the samples were JAHK+ the remaining four were JAHK-. In one JAHK+ sample, the entire RHCE gene was sequenced. The remaining samples were sequenced for exons 1 to 3. A polymerase chain reaction procedure with sequence specific primers was developed for the specific detection of the JAHK allele. RESULTS: Analysis of the entire RHCE gene of one JAHK+ sample showed the expected CcEe-specific nucleotide sequences and revealed an additional nucleotide change (365C>T) in exon 3. This change represented a missense mutation, which led to an amino acid substitution from serine to leucine at position 122 of the RhCE protein. Three JAHK+ samples from two other unrelated families showed the 365C>T mutation and confirmed the association of the Ser122Leu substitution with the JAHK+ phenotype. CONCLUSION: The molecular basis of the JAHK antigen (RH53) is defined by a 365C>T mutation in exon 3 of the RHCE gene leading to the amino acid substitution Ser122Leu. Because the position 122 is predicted to be located in the transmembrane region adjacent to the second loop, the substitution of the neutral serine by the hydrophobic leucine seems to be the cause of the JAHK antigen by a conformational change of the RhCE protein. This structural change may also cause the weakened expression of the C and e antigens observed in JAHK+ individuals. Based on our results it is concluded that the JAHK-specific mutation is associated with a dCe haplotype.
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Eritrócitos/imunologia , Isoantígenos/genética , Sistema do Grupo Sanguíneo Rh-Hr/genética , Substituição de Aminoácidos , Genótipo , Haplótipos , Humanos , MutaçãoRESUMO
BACKGROUND: Lutheran is a complex blood group system consisting of 18 identified antigens. There are four pairs of allelic antigens, whereas others are independently expressed antigens of a high frequency. Lutheran antigens are carried by the Lutheran glycoproteins, which are a product of a single gene LU. STUDY DESIGN AND METHODS: Genomic DNA from 21 individuals of 12 Lutheran phenotypes was used for PCR amplification of selected LU exons that were directly sequenced and compared to control DNA of a common Lutheran phenotype. RESULTS: Lutheran phenotypes were mostly caused by single-nucleotide polymorphisms within LU, resulting in single amino acid changes. The following mutations were observed: in LU:-4, G524A, Arg175Gln; in LU:-5, G326A, Arg109His; in LU:-6,9, C824T, Ser275Phe; in LU:-8,14, T611A, Met204Lys; in LU:-13, three point mutations (C1340T, Ser447Leu, C1671T silent mutation for Ser557 and A1742T, Gln581Leu); in LU:-16, C679T, Arg227Cys; in LU:-17, G340A, Glu114Lys; and in LU:-20, C905T, Thr302Met. Two LU:-12 samples had differing results: one individual had a deletion 99GCGCTT, Arg34 and Leu35, whereas the second LU:-12 sample had a point mutation G419A, Arg140Gln. CONCLUSION: The results revealed the genetic background of 11 Lutheran antigens and suggested their placement on the Lutheran glycoprotein.
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Sistema do Grupo Sanguíneo Lutheran/genética , Polimorfismo de Nucleotídeo Único , Éxons , Humanos , Sistema do Grupo Sanguíneo Lutheran/química , Fenótipo , Polimorfismo de Fragmento de Restrição , Estrutura Terciária de ProteínaRESUMO
McLeod Syndrome (MLS) is a rare X-linked disorder characterized by haemopoietic abnormalities and late-onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453-bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7-year-old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Deleção de Genes , Doenças Hematológicas/genética , Sistema do Grupo Sanguíneo de Kell/genética , Sequência de Bases , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças Neuromusculares/genética , SíndromeRESUMO
BACKGROUND & AIMS: Infection with Helicobacter pylori causes chronic gastritis, and this confers a risk of gastric cancer. Short alleles of the membrane-bound mucin MUC1, which has a large extracellular highly glycosylated domain and is highly polymorphic due to variation in the number of tandemly repeated (TR) 20-amino acid units, have been shown to be associated with gastric cancer. Our aim was to investigate the involvement of MUC1 in chronic gastritis and, by implication, gastric cancer. METHODS: Immunohistochemical analysis was performed on endoscopic biopsy specimens from 95 patients. Gastritis was classified using the Sydney System, and H. pylori status was determined. MUC1 was detected with antibodies against different epitopes of the TR region and the cytoplasmic tail. Southern blot analysis of the MUC1 gene was performed on 57 Northern European patients to determine TR allele lengths. RESULTS: With the TR antibodies, apical staining and some perinuclear staining was seen in 34 of 41 biopsy specimens classified as histologically normal and H. pylori negative. None of the 36 biopsy specimens with gastritis and current H. pylori infection showed apical staining. In contrast, the cytoplasmic tail antibody detected apical staining in both groups. Comparison of the MUC1 allele length distributions between Northern European patients with H. pylori infection and those without H. pylori gastritis showed a statistically significant difference in distribution, with shorter alleles associated with H. pylori gastritis. CONCLUSIONS: Our results suggest that H. pylori interacts with MUC1 and that there are functional allelic differences that affect susceptibility to gastritis.
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Alelos , Gastrite/genética , Gastrite/microbiologia , Infecções por Helicobacter , Helicobacter pylori , Mucina-1/genética , Mucina-1/metabolismo , Sequência de Aminoácidos/genética , Feminino , Gastrite/metabolismo , Gastrite/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo Genético/genética , Valores de ReferênciaRESUMO
Tetraspanins are thought to facilitate the formation of multiprotein complexes at cell surfaces, but evidence illuminating the biologic importance of this role is sparse. Tetraspanin CD151 forms very stable laminin-binding complexes with integrins alpha3beta1 and alpha6beta1 in kidney and alpha3beta1 and alpha6beta4 in skin. It is encoded by a gene at the same position on chromosome 11p15.5 as the MER2 blood group gene. We show that CD151 expresses the MER2 blood group antigen and is located on erythrocytes. We examined CD151 in 3 MER2-negative patients (2 are sibs) of Indian Jewish origin with end-stage kidney disease. In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor. The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140. The resultant truncated protein would lack its integrin-binding domain. We conclude that CD151 is essential for the proper assembly of the glomerular and tubular basement membrane in kidney, has functional significance in the skin, is probably a component of the inner ear, and could play a role in erythropoiesis.