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  • 1.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Mårtensson, A.
    Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, T.
    Department of Biology, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lidén, Annika C.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö.
    Origin of Swedish hemophilia B mutations2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no 11, p. 2001-2008Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: More than 1100 mutations that cause hemophilia B (HB) have been identified. At the same time, specific F9 mutations are present at high frequencies in certain populations, which raise questions about the origin of HB mutations.

    OBJECTIVES: To describe the mutation spectrum of all HB families in Sweden and investigate if mutations appearing in several families are due to independent recurrent mutations (RMs) or to a common mutation event (i.e. are identical by descent (IBD)).

    PATIENTS/METHODS: The registered Swedish HB population consists of patients from 86 families. Mutations were identified by resequencing and identical haplotypes were defined using 74 markers and a control population of 285 individuals. The ages of IBD mutations were estimated using ESTIAGE.

    RESULTS: Out of 77 presumably unrelated patients with substitution mutations, 47 patients (61%) had mutations in common with other patients. Haplotyping of the 47 patients showed that 24 patients had IBD mutations (51%) with estimated ages of between two and 23 generations. A majority of these patients had mild disease. Eight of the 15 mutations observed in more than one family were C>T transitions in CpG sites and all eight were RMs.

    CONCLUSIONS: The association of IBD mutations with a mild phenotype is similar to what has been previously observed in hemophilia A. Noteworthy features of the mutations that are common to more than one family are the equal proportions of patients with RM and IBD mutations and the correlation between the occurrence of RMs and C>T transitions at CpG sites.

  • 2.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, Torbjorn
    Department of Biology, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lidén, Annika C.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Department of Pediatrics and Malmö Center for Thrombosis and Hemostasis, Lund University.
    Origin of Swedish hemophilia A mutations2012In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 10, no 12, p. 2503-2511Article in journal (Refereed)
    Abstract [en]

     Background: Hemophilia A (HA) has a high level of variation within the disease class, with more than 1000 mutations being listed in the HAMSTeRS database. At the same time a number of F8 mutations are present in specific populations at high frequencies. Objectives: The simultaneous presence of large numbers of rare mutations and a small number of high-frequency mutations raises questions about the origins of HA mutations. The present study was aimed at describing the origins of HA mutations in the complete Swedish population. The primary issue was to determine what proportion of identical mutations are identical by descent (IBD) and what proportion are attributable to recurrent mutation events. The age of IBD mutations was also determined. Patients/Methods: In Sweden, the care of HA is centralized, and the Swedish HA population consists of ∼ 750 patients from > 300 families (35% severe, 15% moderate, and 50% mild). Identical haplotypes were defined by single-nucleotide polymorphism and microsatellite haplotyping, and the ages of the mutations were estimated with estiage. Results: Among 212 presumably unrelated patients with substitution mutations, 97 (46%) had mutations in common with other patients. Haplotyping of the 97 patients showed that 47 had IBD mutations (22%) with estimated ages of between two and 35 generations. The frequency of mild disease increased with an increasing number of patients sharing the mutations. Conclusions: A majority of the IBD mutations are mild and have age estimates of a few hundred years, but some could date back to the Middle Ages.

  • 3. Lanke, E.
    et al.
    Johansson, A. M.
    Halldén, Christer
    Department of Clinical Chemistry, University Hospital, Malmö.
    Lethagen, S.
    Genetic analysis of 31 Swedish type 1 von Willebrand disease families reveals incomplete linkage to the von Willebrand factor gene and a high frequency of a certain disease haplotype2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 12, p. 2656-2663Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The most common type of von Willebrand disease (VWD), type 1, has in only a few cases been explained by an identified causative mutation in the von Willebrand factor (VWF) gene. The ABO blood group and other modifier loci outside the VWF gene may contribute to the development of type 1 VWD.

    OBJECTIVES AND METHODS:

    Our aim was to determine whether there was genetic linkage to the VWF gene in 31 Swedish type 1 VWD families. Stringent diagnostic criteria in accordance with ISTH guidelines were used. Genetic linkage was investigated by using two highly informative dinucleotide microsatellite markers, which we have recently identified, located in introns six and 15 of the VWF gene. We also investigated the existence of common disease haplotypes and the relation between type 1 VWD and ABO blood group.

    RESULTS:

    We found genetic linkage to the VWF gene in 27 (87%) of the families. However, in four (13%) of the families, there was clearly no genetic linkage. We found the 4751A>G (Tyr1584Cys) sequence variation in exon 28, which is a common mutation in the Canadian VWD population (14.3%), in only one of the 31 families (3.2%). A possible common mutation was identified in six of the 27 (22%) families with genetic linkage. Blood group O was over-represented among type 1 VWD patients.

    CONCLUSION:

    We conclude that there is linkage between the VWF gene and hereditary type 1 VWD in a majority of families.

  • 4. Lanke, E.
    et al.
    Johansson, A. M.
    Hillarp, A.
    Lethagen, S.
    Zöller, B.
    Dahlbäck, B.
    Halldén, Christer
    Department of Clinical Chemistry, University Hospital, Malmö.
    Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS12004In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 2, no 11, p. 1918-1923Article in journal (Refereed)
    Abstract [en]

    Inherited deficiency of protein S constitutes an important risk factor of venous thrombosis. Many reports have demonstrated that causative mutations in the protein S gene are found only in approximately 50% of the cases with protein S deficiency. It is uncertain whether the protein S gene is causative in all cases of protein S deficiency or if other genes are involved in cases where no mutation is identified. The aim of the current study was to determine whether haplotypes of the protein S gene cosegregate with the disease phenotype in cases where no mutations have been found. Eight protein S-deficient families comprising 115 individuals where previous DNA sequencing had failed to detect any causative mutations were analyzed using four microsatellite markers in the protein S gene region. Co-segregation between microsatellite haplotypes and protein S deficiency was found in seven of the investigated families, one family being uninformative. This suggests that the causative genetic defects are located in or close to the protein S gene in a majority of such cases where no mutations have been found.

  • 5.
    Manderstedt, Eric
    et al.
    Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
    Lind-Halldén, Christina
    Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
    Ljung, Rolf
    Lunds universitet.
    Astermark, Jan
    Skåne University Hospital.
    Halldén, C
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
    Detection of F8 int22h inversions using digital droplet PCR and mile-post assays2020In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 5, p. 1039-1049Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Inversions involving intron 22 (Inv22) of F8 are detected in approximately 45% of all severe hemophilia A patients. Diagnosis is complicated by the large size of the ~9.5 kb int22h repeated sequence which generates the inversions. Methods such as long-range PCR and inverse-shifting PCR are currently used diagnostically, but suffer from low PCR efficiencies and are difficult to standardize.

    OBJECTIVES: To design and validate a sensitive and robust assay for the detection of F8 int22h inversions.

    METHODS: Digital droplet PCR using mile-post assays was used to investigate archival DNA samples.

    RESULTS: The detection of linkage as a function of physical distance between loci was investigated using an anchor locus and mile-post loci located at 1, 6, 12 and 15 kb distances from the anchor locus. The proportion of linked molecules decreased with increasing distance between loci and showed 30-40% linked molecules for loci 12-15 kb apart. Mile-post assays specific for wild type and Inv22 type 1 and 2 chromosomes were then designed and optimized. All three assays showed high specificities and sensitivities, with coefficients of variation < 5% for all assays. Analysis of 106 patients and 20 carrier mothers showed complete concordance with previously known mutation status. The analysis demonstrated the robustness of the assays versus input DNA concentration (6 ng and higher) and level of fragmentation.

    CONCLUSIONS: Digital droplet PCR and mile-post assays can be used to detect F8 int22h inversions. The assay systems are technically simple to perform, highly efficient and robust.

  • 6.
    Manderstedt, Eric
    et al.
    Kristianstad University, Faculty of Natural Sciences, Avdelningen för miljö- och biovetenskap. Kristianstad University, Faculty of Natural Sciences, Forskningsmiljön Biomedicin. Kristianstad University, Plattformen för molekylär analys.
    Lind-Halldén, Christina
    Kristianstad University, Faculty of Natural Sciences, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Sciences, Avdelningen för miljö- och biovetenskap.
    Ljung, Rolf
    Skåne University Hospital.
    Astermark, Jan
    Skåne University Hospital.
    Halldén, Christer
    Kristianstad University, Faculty of Natural Sciences, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Sciences, Avdelningen för miljö- och biovetenskap.
    Droplet digital PCR and mile-post analysis for the detection of F8 int1h inversions2021In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 19, no 3, p. 732-737Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: F8 int1h inversions (Inv1) are detected in 1-2% of severe hemophilia A (HA) patients. Long-range polymerase chain reaction (PCR) and inverse-shifting PCR have been used to diagnose these inversions.

    OBJECTIVES: To design and validate a sensitive and robust assay for detection of F8 Inv1 inversions.

    METHODS: Archival DNA samples were investigated using mile-post assays and droplet digital PCR.

    RESULTS: Mile-post assays for Inv1 showing high specificities and sensitivities were designed and optimized. Analysis of four patients, two carrier mothers and 40 healthy controls showed concordance with known mutation status with one exception. One patient had a duplication involving exons 2-22 of the F8 gene instead of an Inv1 mutation. DNA mixtures with different proportions of wild type and Inv1 DNA correlated well with the observed relative linkage for both wild type and Inv1 assays and estimated the limit of detection of these assays to 2% of the rare chromosome.

    CONCLUSIONS: The mile-post strategy has several inherent control systems. The absolute counting of target molecules by both assays enables determination of template quantity, detection of copy number variants and rare variants occurring in primer and probe annealing sites and estimation of DNA integrity through the observed linkage. The presented Inv1 mile-post analysis offers sensitive and robust detection and quantification of the F8 int1h inversions and other rearrangements involving intron 1 in patients and their mothers.

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  • 7.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Hellwage, J
    Zipfel, P F
    Sjoholm, A G
    Iancu, R
    Karpman, D
    Factor H binds to washed human platelets2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 1, p. 154-162Article in journal (Refereed)
    Abstract [en]

    Background: Factor H regulates the alternative pathway of complement. The protein has three heparin-binding sites, is synthesized primarily in the liver and copurifies from platelets with thrombospondin-1. Factor H mutations at the C-terminus are associated with atypical hemolytic uremic syndrome, a condition in which platelets are consumed. Objectives The aim of this study was to investigate if factor H interacts with platelets.

    Methods: Binding of factor H, recombinant G or N-terminus constructs and a C-terminus mutant to washed (plasma and complement-free) platelets was analyzed by flow cytometry. Binding of factor H and constructs to thrombospondin-1 was measured by surface plasmon resonance.

    Results: Factor H bound to platelets in a dose-dependent manner. The major binding site was localized to the C-terminus. The interaction was partially blocked by heparin. Inhibition with anti-GPIIb/IIIa, or with fibrinogen, suggested that the platelet GPIIb/IIIa receptor is involved in factor H binding. Factor H binds to thrombospondin-1. Addition of thrombospondin-1 increased factor H binding to platelets. Factor H mutated at the C-terminus also bound to platelets, albeit to a significantly lesser degree.

    Conclusions: This study reports a novel property of factor H, i.e. binding to platelets, either directly via the GPIIb/IIIa receptor or indirectly via thrombospondin-1, in the absence of complement. Binding to platelets was mostly mediated by the C-terminal region of factor H and factor H mutated at the C-terminus exhibited reduced binding.

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