Publications by authors named "Mattias Jansson"

22 Publications

  • Page 1 of 1

A hemizygous mutation in the FOXP3 gene (IPEX syndrome) resulting in recurrent X-linked fetal hydrops: a case report.

BMC Med Genomics 2021 Feb 26;14(1):58. Epub 2021 Feb 26.

Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: Fetal hydrops is excessive extravasation of fluid into the third space in a fetus, which could be due to a wide differential of underlying pathology. IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome primarily affects males. It is a monogenic primary immunodeficiency syndrome of X-linked recessive inheritance due to FOXP3 gene variants. It is characterised by the development of multiple autoimmune disorders in affected individuals.

Case Presentation: We present a rare cause of male fetal hydrops in the context of IPEX syndrome and discuss FOXP3 gene variants as a differential for 'unexplained' fetal hydrops that may present after the first trimester.

Discussion And Conclusions: In all similar cases, the pathological process begins during intrauterine life. Furthermore, there are no survivors described. Consequently, this variant should be considered as a severe one, associated with intrauterine life onset and fatal course, i.e., the most severe IPEX phenotype.
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http://dx.doi.org/10.1186/s12920-021-00901-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908803PMC
February 2021

Self-assembled nanodisks in coaxial GaAs/GaAsBi/GaAs core-multishell nanowires.

Nanoscale 2020 Oct;12(40):20849-20858

Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.

III-V semiconductor nanowires (NWs), such as those based on GaAs, are attractive for advanced optoelectronic and nanophotonic applications. The addition of Bi into GaAs offers a new avenue to enhance the near-infrared device performance and to add new functionalities, by utilizing the remarkable valence band structure and the giant bowing in the bandgap energy. Here, we report that alloying with Bi also induces the formation of optically-active self-assembled nanodisks caused by Bi segregation. They are located in the vicinity to the 112 corners of the GaAsBi shell and are restricted to twin planes. Furthermore, the Bi composition in the disks is found to correlate with their lateral thickness. The higher Bi composition in the disks with respect to the surrounding matrix provides a strong confinement for excitons along the NW axis, giving rise to narrow emission lines (<450 μeV) with the predominant emission polarization orthogonal to the NW axis. Our findings, therefore, open a new possibility to fabricate self-assembled quantum structures by combining advantages of dilute bismide alloys and lattice engineering in nanowires.
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http://dx.doi.org/10.1039/d0nr05488gDOI Listing
October 2020

Paternal somatogonadal COL2A1 mosaicism causing recurrence of severe type 2 collagenopathy.

Am J Med Genet A 2020 09 9;182(9):2191-2194. Epub 2020 Jul 9.

Viapath Genetics Laboratory, 7th Floor Borough Wing, Guys Hospital, London, UK.

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http://dx.doi.org/10.1002/ajmg.a.61763DOI Listing
September 2020

Effects of thermal annealing on localization and strain in core/multishell GaAs/GaNAs/GaAs nanowires.

Sci Rep 2020 May 19;10(1):8216. Epub 2020 May 19.

Department of Physics, Chemistry and Biology, Linköping University, 581 83, Linköping, Sweden.

Core/shell nanowire (NW) heterostructures based on III-V semiconductors and related alloys are attractive for optoelectronic and photonic applications owing to the ability to modify their electronic structure via bandgap and strain engineering. Post-growth thermal annealing of such NWs is often involved during device fabrication and can also be used to improve their optical and transport properties. However, effects of such annealing on alloy disorder and strain in core/shell NWs are not fully understood. In this work we investigate these effects in novel core/shell/shell GaAs/GaNAs/GaAs NWs grown by molecular beam epitaxy on (111) Si substrates. By employing polarization-resolved photoluminescence measurements, we show that annealing (i) improves overall alloy uniformity due to suppressed long-range fluctuations in the N composition; (ii) reduces local strain within N clusters acting as quantum dot emitters; and (iii) leads to partial relaxation of the global strain caused by the lattice mismatch between GaNAs and GaAs. Our results, therefore, underline applicability of such treatment for improving optical quality of NWs from highly-mismatched alloys. They also call for caution when using ex-situ annealing in strain-engineered NW heterostructures.
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http://dx.doi.org/10.1038/s41598-020-64958-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237432PMC
May 2020

Increasing N content in GaNAsP nanowires suppresses the impact of polytypism on luminescence.

Nanotechnology 2019 Oct 26;30(40):405703. Epub 2019 Jun 26.

Department of Physics, Chemistry and Biology, Linköping University, SE-58183 Linköping, Sweden.

Cathodoluminescence (CL) and micro-photoluminescence spectroscopies are employed to investigate effects of structural defects on carrier recombination in GaNAsP nanowires (NWs) grown by molecular beam epitaxy on Si substrates. In the NWs with a low N content of 0.08%, these defects are found to promote non-radiative (NR) recombination, which causes spatial variation of the CL peak position and its intensity. Unexpectedly, these detrimental effects can be suppressed even by a small increase in the nitrogen composition from 0.08% to 0.12%. This is attributed to more efficient trapping of excited carriers/excitons to the localized states promoted by N-induced localization and also the presence of other NR channels. At room temperature, the structural defects no longer dominate in carrier recombination even in the NWs with the lower nitrogen content, likely due to increasing importance of other recombination channels. Our work underlines the need in eliminating important thermally activated NR defects, other than the structural defects, for future optoelectronic applications of these NWs.
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http://dx.doi.org/10.1088/1361-6528/ab2cdbDOI Listing
October 2019

Post-mortem Characterisation of a Case With an Variant, Agenesis of the Corpus Callosum and Neuronal Heterotopia.

Front Physiol 2019 24;10:623. Epub 2019 May 24.

Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St Thomas' Hospital, London, United Kingdom.

Cytoplasmic Actin Gamma 1 () gene variant are autosomal dominant and can cause CNS anomalies (Baraitser Winter Malformation Syndrome; BWMS). anomalies in offspring include agenesis of the corpus callosum (ACC) and neuronal heterotopia which are ectopic nodules of nerve cells that failed to migrate appropriately. Subcortical and periventricular neuronal heterotopia have been described previously in association with ACC. In this case report, we investigated a neonatal brain with an gene variant and a phenotype of ACC, and neuronal heterotopia (ACC-H) which was diagnosed on antenatal MR imaging and was consistent with band heterotopia seen on post-mortem brain images. Histologically clusters of neurons were seen in both the subcortical and periventricular white matter (PVWM) brain region that coincided with impaired abnormalities in glial formation. Immunohistochemistry was performed on paraffin-embedded brain tissue blocks from this case with variant and an age-matched control. Using tissue sections from the frontal lobe, we examined the distribution of neuronal cells (HuC/HuD, calretinin, and parvalbumin), growth cone (drebrin), and synaptic proteins (synaptophysin and SNAP-25). Additionally, we investigated how the variant altered astroglia (nestin, GFAP, vimentin); oligodendroglia (OLIG2) and microglia (Iba-1) in the corpus callosum, cortex, caudal ganglionic eminence, and PVWM. As predicted in the variant case, we found a lack of midline radial glia and glutamatergic fibers. We also found disturbances in the cortical region, in glial cells and a lack of extracellular matrix components in the variant. The caudal ganglionic eminence and the PVWM regions in the variant lacked several cellular components that were identified in a control case. Within the neuronal heterotopia, we found evidence of glutamatergic and GABAergic neurons with apparent synaptic connections. The data presented from this case study with BWMS with variants in the gene provides insight as to the composition of neuronal heterotopia, and how disturbances of important migratory signals may dramatically affect ongoing brain development.
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http://dx.doi.org/10.3389/fphys.2019.00623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558385PMC
May 2019

Flow Cytometric Measurement of Blood Cells with BCR-ABL1 Fusion Protein in Chronic Myeloid Leukemia.

Sci Rep 2017 04 4;7(1):623. Epub 2017 Apr 4.

Dept. of Immunology, Genetics & Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Chronic myeloid leukemia (CML) is characterized in the majority of cases by a t(9;22)(q34;q11) translocation, also called the Philadelphia chromosome, giving rise to the BCR-ABL1 fusion protein. Current treatment with tyrosine kinase inhibitors is directed against the constitutively active ABL1 domain of the fusion protein, and minimal residual disease (MRD) after therapy is monitored by real-time quantitative PCR (RQ-PCR) of the fusion transcript. Here, we describe a novel approach to detect and enumerate cells positive for the BCR-ABL1 fusion protein by combining the in situ proximity ligation assay with flow cytometry as readout (PLA-flow). By targeting of the BCR and ABL1 parts of the fusion protein with one antibody each, and creating strong fluorescent signals through rolling circle amplification, PLA-flow allowed sensitive detection of cells positive for the BCR-ABL1 fusion at frequencies as low as one in 10,000. Importantly, the flow cytometric results correlated strongly to those of RQ-PCR, both in diagnostic testing and for MRD measurements over time. In summary, we believe this flow cytometry-based method can serve as an attractive approach for routine measurement of cells harboring BCR-ABL1 fusions, also allowing simultaneously assessment of other cell surface markers as well as sensitive longitudinal follow-up.
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http://dx.doi.org/10.1038/s41598-017-00755-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429594PMC
April 2017

Dilute Nitride Nanowire Lasers Based on a GaAs/GaNAs Core/Shell Structure.

Nano Lett 2017 03 8;17(3):1775-1781. Epub 2017 Feb 8.

Department of Physics, Chemistry and Biology, Linköping University , 58183, Linköping, Sweden.

Nanowire (NW) lasers operating in the near-infrared spectral range are of significant technological importance for applications in telecommunications, sensing, and medical diagnostics. So far, lasing within this spectral range has been achieved using GaAs/AlGaAs, GaAs/GaAsP, and InGaAs/GaAs core/shell NWs. Another promising III-V material, not yet explored in its lasing capacity, is the dilute nitride GaNAs. In this work, we demonstrate, for the first time, optically pumped lasing from the GaNAs shell of a single GaAs/GaNAs core/shell NW. The characteristic "S"-shaped pump power dependence of the lasing intensity, with the concomitant line width narrowing, is observed, which yields a threshold gain, g, of 3300 cm and a spontaneous emission coupling factor, β, of 0.045. The dominant lasing peak is identified to arise from the HE cavity mode, as determined from its pronounced emission polarization along the NW axis combined with theoretical calculations of lasing threshold for guided modes inside the nanowire. Even without intentional passivation of the NW surface, the lasing emission can be sustained up to 150 K. This is facilitated by the improved surface quality due to nitrogen incorporation, which partly suppresses the surface-related nonradiative recombination centers via nitridation. Our work therefore represents the first step toward development of room-temperature infrared NW lasers based on dilute nitrides with extended tunability in the lasing wavelength.
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http://dx.doi.org/10.1021/acs.nanolett.6b05097DOI Listing
March 2017

Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia.

Leuk Lymphoma 2013 Aug 25;54(8):1769-79. Epub 2013 Feb 25.

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.
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http://dx.doi.org/10.3109/10428194.2013.764418DOI Listing
August 2013

Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection.

Oncoimmunology 2012 Jan;1(1):18-27

Department of Clinical and Experimental Medicine; Division of Cell Biology; Linköping University; Linköping, Sweden.

Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1-2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16-1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.
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http://dx.doi.org/10.4161/onci.1.1.18400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376971PMC
January 2012

IGHV3-21 gene frequency in a Swedish cohort of patients with newly diagnosed chronic lymphocytic leukemia.

Clin Lymphoma Myeloma Leuk 2012 Jun 29;12(3):201-6. Epub 2012 Mar 29.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Department of Biological Sciences, Institute of Technology, Dublin, Ireland.

Unlabelled: The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%)IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status.

Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21.

Materials And Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed.

Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment.

Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status.
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http://dx.doi.org/10.1016/j.clml.2012.01.009DOI Listing
June 2012

Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia.

Haematologica 2011 Aug 5;96(8):1161-9. Epub 2011 May 5.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Background: High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.

Design And Methods: We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years.

Results: At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV.

Conclusions: Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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http://dx.doi.org/10.3324/haematol.2010.039768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148910PMC
August 2011

LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia.

Haematologica 2011 Aug 20;96(8):1153-60. Epub 2011 Apr 20.

Dept. of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Background: The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.

Design And Methods: Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.

Results: High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.

Conclusions: LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.
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http://dx.doi.org/10.3324/haematol.2010.039396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148909PMC
August 2011

High-density screening reveals a different spectrum of genomic aberrations in chronic lymphocytic leukemia patients with 'stereotyped' IGHV3-21 and IGHV4-34 B-cell receptors.

Haematologica 2010 Sep 26;95(9):1519-25. Epub 2010 Apr 26.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751-85 Uppsala, Sweden.

Background: The existence of multiple subsets of chronic lymphocytic leukemia expressing 'stereotyped' B-cell receptors implies the involvement of antigen(s) in leukemogenesis. Studies also indicate that 'stereotypy' may influence the clinical course of patients with chronic lymphocytic leukemia, for example, in subsets with stereotyped IGHV3-21 and IGHV4-34 B-cell receptors; however, little is known regarding the genomic profile of patients in these subsets.

Design And Methods: We applied 250K single nucleotide polymorphism-arrays to study copy-number aberrations and copy-number neutral loss-of-heterozygosity in patients with stereotyped IGHV3-21 (subset #2, n=29), stereotyped IGHV4-34 (subset #4, n=17; subset #16, n=8) and non-subset #2 IGHV3-21 (n=13) and non-subset #4/16 IGHV4-34 (n=34) patients.

Results: Over 90% of patients in subset #2 and non-subset #2 carried copy-number aberrations, whereas 75-76% of patients in subset #4 and subset #16 showed copy-number aberrations. Subset #2 and non-subset #2 patients also displayed a higher average number of aberrations compared to patients in subset #4. Deletion of 13q was the only known recurrent aberration detected in subset #4 (35%); this aberration was even more frequent in subset #2 (79%). del(11q) was more frequent in subset #2 and non-subset #2 (31% and 23%) patients than in subset #4 and non-subset #4/16 patients. Recurrent copy-number neutral loss-of-heterozygosity was mainly detected on chromosome 13q, independently of B-cell receptor stereotypy.

Conclusions: Genomic aberrations were more common in subset #2 and non-subset #2 than in subset #4. The particularly high frequency of del(11q) in subset #2 may be linked to the adverse outcome reported for patients in this subset. Conversely, the lower prevalence of copy-number aberrations and the absence of poor-prognostic aberrations in subset #4 may reflect an inherently low-proliferative disease, which would prevent accumulation of genomic alterations.
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http://dx.doi.org/10.3324/haematol.2009.021014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930953PMC
September 2010

Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia.

Leuk Res 2010 Mar 1;34(3):335-9. Epub 2009 Jul 1.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

The 309T>G polymorphism in the promoter region of the MDM2 gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.
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http://dx.doi.org/10.1016/j.leukres.2009.06.006DOI Listing
March 2010

Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms.

Genes Chromosomes Cancer 2008 Aug;47(8):697-711

Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Hematology and Transplantation, Lund University, Lund, Sweden.

Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.
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http://dx.doi.org/10.1002/gcc.20575DOI Listing
August 2008

The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia.

Leuk Res 2008 Jun 19;32(6):984-7. Epub 2007 Nov 19.

Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL.
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http://dx.doi.org/10.1016/j.leukres.2007.10.003DOI Listing
June 2008

The promoter of inducible nitric oxide synthase implicated in glaucoma based on genetic analysis and nuclear factor binding.

Mol Vis 2005 Nov 4;11:950-7. Epub 2005 Nov 4.

Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Purpose: Nitric oxide has many beneficial functions in the human body at the right amounts, but it can also be hazardous if it is produced in amounts more than needed and has therefore been studied in relation to several neurological and non-neurological disorders. In vitro and in vivo studies demonstrate a connection between the inducible form of Nitric Oxide Synthase, iNOS, and the neuropathological disorder glaucoma, one of the major causes of blindness in the world. In this study, we sought to establish the genetic association between iNOS and primary open angle glaucoma, POAG, and to find the functional element(s) connected with the pathogenesis of the disease.

Methods: Two microsatellites, 1 insertion/deletion, and 8 single nucleotide polymorphisms (SNPs) in the regulatory region of iNOS were genotyped in 200 POAG patients and 200 age-matched controls. Also, the CCTTT-microsatellite was examined for its protein-binding capability in an electrophoretic mobility shift assay, EMSA.

Results: There was a significant difference in allele distribution of the CCTTT-microsatellite, between patients and controls. (CCTTT)14, which has been reported to have a higher activity in a reporter-construct, was significantly more abundant in POAG patients, while (CCTTT)10 and (CCTTT)13 were less common. In EMSA, the (CCTTT)14 allele exhibited specific binding of nuclear proteins.

Conclusions: These results, together with other studies on this gene and the CCTTT-microsatellite, establish, for the first time, a genetic association of iNOS with POAG and suggest a regulatory function for the microsatellite.
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November 2005

Analysis of rare variants and common haplotypes in the optineurin gene in Swedish glaucoma cases.

Ophthalmic Genet 2005 Jun;26(2):85-9

Department of Genetics and Pathology Unit of Medical Genetics, Uppsala University, SE-751 85 Uppsala, Sweden.

Objective: Glaucoma, a leading cause of blindness in the world, is characterized by neuropathy of the retinal ganglion cells and the optic nerve. Recently, sequence alterations in the optineurin gene were shown to be associated with the disease in families with primarily normal tension glaucoma.

Methods: In the present study, 200 patients with primary open-angle glaucoma, 200 patients with exfoliative glaucoma, and 200 matched controls were tested for alterations in the coding sequences using denaturing high-performance liquid chromatography and sequencing. In addition, single nucleotide polymorphisms distributed throughout the gene were typed and haplotypes were constructed.

Results: No disease-causing alterations were found in either of the patient cohorts. The risk-associated allele M98K was found in equal amounts in both patients and controls. Analysis of haplotype frequencies and distribution revealed high haplotype diversity but no differences between patients and controls.

Conclusion: These experiments show no association between optineurin and our Swedish cohorts of high-pressure glaucoma cases, either in coding sequence or in haplotype frequency and distribution.
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http://dx.doi.org/10.1080/13816810490967953DOI Listing
June 2005

Analysis of the Glutathione S-transferase M1 gene using pyrosequencing and multiplex PCR--no evidence of association to glaucoma.

Exp Eye Res 2003 Aug;77(2):239-43

Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala SE-751 85, Sweden.

The Glutathione S-transferase M1 (GSTM1) gene is reported to be involved in glaucoma, an eye disease with a largely unknown mechanism. The gene is polymorphic and three alleles have been characterized. These are one complete deletion of the gene, GSTM1*0, and two alleles differing only in a single amino acid substitution, GSTM1*A and *B. The two latter alleles seem to have equivalent function. Approximately 45% of the European populations are GSTM1 positive. An Estonian study has found that 60% of the glaucoma patients are GSTM1 positive as compared to 45% of controls (P=0.002). We genotyped 200 primary open angle glaucoma patients (POAG), 188 exfoliative glaucoma patients and 200 matched controls using multiplex PCR and pyrosequencing. Forty four per cent of the POAG patients and exfoliative glaucoma patients, and 44.5% of the matched controls were GSTM1 positive. Using pyrosequencing we were able to determine if the patients were homo- or hemizygous for the GSTM1 gene. Five per cent of the POAG patients, 7.4% of the exfoliative glaucoma patients and 4.6% of the controls were homozygous for the presence of the GSTM1 gene. There is no evidence of association between GSTM1 and glaucoma in the Swedish population.
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http://dx.doi.org/10.1016/s0014-4835(03)00109-xDOI Listing
August 2003

Allelic variants in the MYOC/TIGR gene in patients with primary open-angle, exfoliative glaucoma and unaffected controls.

Ophthalmic Genet 2003 Jun;24(2):103-10

Department of Genetics and Pathology, Unit of Clinical Genetics, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

One of the leading causes of blindness in the world is glaucoma. The most common form is primary open-angle glaucoma (POAG). The only gene identified so far as being associated with POAG is the MYOC gene; 2-4% of the patients have been reported to carry mutations in this gene. Exfoliative glaucoma is a secondary glaucoma, in which one of the symptoms is exfoliations on the lens capsule and anterior segment of the eye. No gene has been identified as being associated with this variant. The aim of the present study was to analyze Swedish patient material for allelic variants and mutations in the coding region of the MYOC gene. Two hundred patients with POAG and 200 with exfoliative glaucoma were analyzed using enzymatic cleavage assay and denaturing high-performance liquid chromatography (dHPLC). An age-matched control group (n = 200), in whom glaucoma had been excluded, was also analyzed using dHPLC. Eight allele variants were identified, two of which were determined to be disease-causing mutations. These two disease-causing mutations were only found in POAG patients, indicating a prevalence of 1% in this patient group. This frequency is lower than that reported in other studies of other populations. No disease-causing mutations were found in the exfoliative glaucoma patients, indicating a fundamentally different genetic basis for that glaucoma variant.
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http://dx.doi.org/10.1076/opge.24.2.103.13997DOI Listing
June 2003

Evaluation of the Oculomedin gene in the etiology of primary open angle and exfoliative glaucoma.

Mol Vis 2003 Mar 24;9:93-5. Epub 2003 Mar 24.

Department of Genetics and Pathology, Unit of Clinical Genetics, Uppsala University, Uppsala, Sweden.

Purpose: Glaucoma is a disease of the retinal ganglion cells leading to reduction of peripheral vision. It is often associated with an increase in intraocular pressure, leading to mechanical stress of tissues. The oculomedin gene is activated by such stretching and is therefore a candidate for causing glaucoma.

Methods: The coding sequence and part of the promoter was screened for sequence variants in Swedish cohorts of primary open angle glaucoma, exfoliative glaucoma, and matched controls.

Results: Only rare variants were detected in the patient material.

Conclusions: There was no evidence that the oculomedin gene participates in the etiology of glaucoma.
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March 2003