| 1. |
- Bena, Frederique, et al.
(författare)
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Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature
- 2013
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 162B:4, s. 388-403
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders.
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| 2. |
- Hellberg, Åsa, et al.
(författare)
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P1PK: the blood group system that changed its name and expanded.
- 2013
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Ingår i: Immunohematology. - 0894-203X. ; 29:1, s. 25-33
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Tidskriftsartikel (refereegranskat)abstract
- The antigens in the P1PK blood group system are carried on glycosphingolipids. The system currently includes three different antigens, P1, Pk, and NOR. The P1 antigen was disovered in 1927 by Landsteiner and Levine, and Pk and NOR were described in 1951 and 1982, respectively. As in the ABO system, naturally occurring antibodies of the immunoglobulin (Ig) M or IgG class, against the missing carbohydrate structures, can be present in the sera of people lacking the corresponding antigen. Anti-P1 is generally a weak and cold-reactive antibody not implicated in hemolytic transfusion reaction (HTR) or hemolytic disease of the fetus and newborn while Pk antibodies can cause HTR, and anti-NOR is regarded as a polyagglutinin. A higher frequency of miscarriage is seen in women with the rare phenotypes p, P1k, and P2k. Furthermore, the Pk and P1 antigens have wide tissue distributions and can act as host receptors for various pathogens and toxins. Why p individuals lack not only Pk and P expression but also P1 has been a longstanding enigma. Recently, it was shown that the same A4GALT-encoded galactosyltransferase synthesizes both the P1 and Pk antigens and that a polymorphism in a new exon in this gene predicts the P1 and P2 phenotypes.
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| 3. |
- Irshaid, N M, et al.
(författare)
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Genomic typing of the Kidd blood group locus by a single-tube allele-specific primer PCR technique
- 1998
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 102:4, s. 1010-1014
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Tidskriftsartikel (refereegranskat)abstract
- The Kidd (JK) blood group system is clinically important in transfusion medicine. Alloantibodies to antigens in this system may be produced following blood transfusion or during pregnancy and can result in serious haemolytic transfusion reactions and haemolytic disease of the newborn (HDN). JK antigens on erythrocytes are carried by glycoproteins with the capacity to transport urea through cell membranes. cDNA complementary to mRNA transcribed at the JK locus was cloned in 1994. The molecular basis of the Jk(a)/Jk(b) blood group polymorphism was recently shown to be a single nucleotide substitution predicting an amino acid change (Asp280Asn) in an extracellular loop of the JK glycoprotein. After confirmation of the JK gene polymorphism we developed a rapid and robust technique for JK genotyping with allele-specific primers in a single-tube PCR. In addition, a 217 bp intron located at nucleotides 811-812 in the JK gene was found and sequenced. The genotyping test was validated with samples from 106 Caucasian Swedish and 13 Black South African random blood donors. Complete phenotype-genotype correlations were obtained. However, four Jk(a-b-) samples of Polynesian and Finnish origin typed as Jk(b)Jk(b). Potential use of the presented method can be predicted in clinical transfusion medicine including prenatal determination of the JK genotype in a fetus at risk for HDN caused by JK antibodies.
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| 4. |
- Olsson, Martin L, et al.
(författare)
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An Ael allele-specific nucleotide insertion at the blood group ABO locus and its detection using a sequence-specific polymerase chain reaction
- 1995
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 216:2, s. 642-647
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Tidskriftsartikel (refereegranskat)abstract
- Genomic DNA from each of four Acl individuals (genotypes AO1, AO1var, AO2) and one AclB individual was used as a template for amplifying exons 6 and 7 of the ABO genes, which were subsequently sequenced. In all the Ael alleles a single nucleotide insertion, compared to the A consensus sequence, was observed that would alter the amino acid sequence of the glycosyltransferase immediately after its postulated nucleotide sugar binding site and furthermore extend the translated protein by 37 amino acids (16 more than the A2 enzyme). A sequence-specific primer PCR assay was developed to detect the nucleotide insertion. It was possible to differentiate all 20 serologically defined Acl/AclB individuals available from 145 blood donors with normal ABO phenotypes and genotypes and 26 individuals with various A subgroups other than A1, A2 and Acl. This mutation explains the Acl phenotype and forms the basis of a method for detecting the Ael allele.
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| 5. |
- Rajnavolgyi, E, et al.
(författare)
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A repetitive sequence of Epstein-Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DR-restricted CD4(+) T lymphocytes
- 2000
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377 .- 0953-8178. ; 12:3, s. 281-293
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Tidskriftsartikel (refereegranskat)abstract
- Most human adults carry the Epstein-Barr virus (EBV) and develop immunological memory against the structural and the virus-encoded cellular proteins. The EBV nuclear antigen 6 (EBNA6) elicits cytotoxic T cell responses and it also maintains a persistent antibody response. The majority of sera from EBV-seropositive individuals reacts with a synthetic peptide, p63, comprising 21 amino acids of a repetitive region of EBNA6. CD4(+) T lymphocytes, with specificity for p63, could be recalled from the T cell repertoire of EBV carriers that expressed certain HLA-DR allotypes which were identified as good binders of p63 by an in vitro flow cytometric assay. Analysis of the HLA-DR/p63 interaction by molecular mechanics calculations indicated the presence of multiple overlapping epitopes which were predicted to bind in a HLA-DRB1 allo- and subtype-specific manner. Specific activation of p63-selected long-term CD4(+) T cell cultures resulted in a proliferative response, in the production of IL-2 and in the secretion of high levels of tumor necrosis factor as measured by bioassays. Proliferation and cytokine production of p63-specific T cells could be induced by p63-loaded HLA-DR-matched antigen-presenting cells and by B cells co-expressing relevant HLA-DR molecules and EBNA6. Our results show that peptides of an EBNA6 repeat region induce CD4(+) T cells which can react with EBNA6-carrying cells in many individuals. We suggest that these T(h) cells may be important in conditioning dendritic cells for initiation potent virus-specific immune responses, provide help for EBV-specific B cells, drive IgG isotype switch and support the sustained effector function of memory cytotoxic T lymphocytes.
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| 6. |
- Schoumans, Jacqueline, et al.
(författare)
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Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients
- 2007
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 15:2, s. 143-149
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Tidskriftsartikel (refereegranskat)abstract
- Cornelia de Lange syndrome (CdLS; OMIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by distinctive dysmorphic facial features, severe growth and developmental delay and abnormalities of the upper limbs. About 50% of CdLS patients have been found to have heterozygous mutations in the NIPBL gene and a few cases were recently found to be caused by mutations in the X-linked SMC1L1 gene. We performed a mutation screening of all NIPBL coding exons by direct sequencing in 11 patients (nine sporadic and two familial cases) diagnosed with CdLS in Sweden and detected mutations in seven of the cases. All were de novo, and six of the mutations have not been previously described. Four patients without identifiable NIPBL mutations were subsequently subjected to multiplex ligation-dependent probe amplification analysis to exclude whole exon deletions/duplications of NIPBL. In addition, mutation analysis of the 5' untranslated region (5' UTR) of NIPBL was performed. Tiling resolution array comparative genomic hybridization analysis was carried out on these four patients to detect cryptic chromosome imbalances and in addition the boys were screened for SMC1L1 mutations. We found a de novo 9p duplication with a size of 0.6 Mb in one of the patients with a CdLS-like phenotype but no mutations were detected in SMC1L1. So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes. However, in a considerable proportion of individuals demonstrating the CdLS phenotype, mutations in any of these two genes are not found and other potential loci harboring additional CdLS-causing genes should be considered.
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| 7. |
- Storry, Jill, et al.
(författare)
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Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 537-U109
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Tidskriftsartikel (refereegranskat)abstract
- The Vel antigen is present on red blood cells (RBCs) from all humans except rare Vel-negative individuals who can form antibodies to Vel in response to transfusion or pregnancy. These antibodies may cause severe hemolytic reactions in blood recipients. We combined SNP profiling and transcriptional network modeling to link the Vel-negative phenotype to SMIM1, located in a 97-kb haplotype block on chromosome 1p36. This gene encodes a previously undiscovered, evolutionarily conserved transmembrane protein expressed on RBCs. Notably, 35 of 35 Vel-negative individuals were homozygous for a frameshift deletion of 17 bp in exon 3. Functional studies using antibodies raised against SMIM1 peptides confirmed a null phenotype in RBC membranes, and SMIM1 overexpression induced Vel expression. Genotype screening estimated that similar to 1 of 17 Swedish blood donors is a heterozygous deletion carrier and similar to 1 of 1,200 is a homozygous deletion knockout and enabled identification of Vel-negative donors. Our results establish SMIM1 as a new erythroid gene and Vel as a new blood group system.
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| 8. |
- Swedin, Agneta, et al.
(författare)
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Clinical utility of immunoglobulin heavy chain gene rearrangement identification for tumour cell detection in multiple myeloma
- 1998
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 103:4, s. 1145-1151
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Tidskriftsartikel (refereegranskat)abstract
- In an attempt to define the clinical utility of immunoglobulin heavy chain (IgH) gene rearrangement identification for tumour cell detection in multiple myeloma, we investigated 36 consecutive newly diagnosed patients intended for high-dose chemotherapy in a study protocol. After identification of the IgH rearrangement, an allele specific oligonucleotide (ASO) was constructed and used in a semiquantative PCR for minimal residual disease (MRD) evaluation. The myeloma-specific IgH gene rearrangement could be identified and an ASO primer constructed in 24 (67%) of the patients. All of these patients underwent transplantation; 22 were autologous, of whom three had PCR-negative stem cell harvests, and two were allogeneic. 10 patients achieved a clinical complete response (CR) and five were PCR negative in sequential bone marrow analyses. In patients not achieving CR, PCR negativity was occasionally found, but in general the PCR results reflected the clinical status of the patients. No consistent relationship between the bone marrow MRD status and the clinical course was found, and early relapses occurred also in PCR-negative patients.
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| 9. |
- Thuresson, Britt, et al.
(författare)
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A novel B(weak) hybrid allele lacks three enhancer repeats but generates normal ABO transcript levels.
- 2012
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Ingår i: Vox Sanguinis. - : Wiley. - 1423-0410 .- 0042-9007. ; 102:1, s. 55-64
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Weak expression of A/B histo-blood group antigens is often explained by single nucleotide substitutions at the ABO locus. However, hybrid alleles containing segments from different ABO alleles can result in unexpected phenotypes and may complicate genotype analysis. We investigated the basis of weak B phenotype in a referred sample. Materials and Methods A healthy young woman was serologically phenotyped as AB(weak) and RBCs were characterized by flow cytometry. All seven ABO exons, five introns plus the 5'-region including the CCAAT-binding factor/Nuclear Factor Y (CBF/NF-Y) binding enhancer were sequenced. ABO transcript levels were measured in fresh peripheral blood samples. Expression of B antigen was semiquantified following transfection of HeLa cells. Results A new B(weak) allele with 53G>T resulted in a characteristic pattern of moderately weakened B antigen expression on RBCs. Its sequence revealed a novel hybrid between O(2) [O03] and B [B101] alleles with a crossingover region in intron 4 as defined by allele-specific polymorphisms. B transcript levels were similar to normal controls despite the O(2) -related single CBF/NF-Y-binding 43-bp motif in the enhancer region. Expression of the glycosyltransferase including the O(2) -specific Arg18Leu substitution resulted in a slight decrease in B-antigen-positive cells. Conclusion We describe here the first hybrid between an O(2) and a B allele and characterized the associated decrease in B antigen expression. Although it lacks three enhancer repeat units compared to common B alleles, the resulting transcript level was unaltered. This study challenges previous suggestions that the number of 43-bp motifs in the ABO enhancer determines transcription rates in erythroid cells.
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| 10. |
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