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  • 1.
    Jakobson Mo, Susanna
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Axelsson, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    J. Stiernman, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Larsson, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    af Bjerkén, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Bäckström, David C.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Gabrielsson Kellgren, Therese
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Varrone, Andrea
    Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Stockholm, Sweden.
    Riklund, Katrine
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    VNTR polymorphism in the SLC6A3 gene does not influence dopamine transporter availability measured by [18F]FE-PE2I PET or [123I]FP-Cit SPECT2022Ingår i: Nuclear medicine communications, ISSN 0143-3636, E-ISSN 1473-5628, Vol. 43, nr 3, s. 247-255Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To investigate the potential impact of polymorphism in the 3'-untranslated region (3'UTR) of the SLC6A3 gene (DAT1) on normal variation in dopamine transporter (DAT) imaging with [18F]FE-PE2I PET and [123I]FP-Cit SPECT.

    METHODS: Thirty-six individuals (mean age 70.4±5.4 years) with normal [18F]FE-PE2I PET and [123I]FP-Cit SPECT were genotyped for variable number of tandem repeats (VNTR) in the 3′UTR of the DAT1 gene. The DAT-availability in the caudate and putamen as measured with [18F]FE-PE2I PET and [123I]FP-Cit SPECT, as well as in the substantia nigra with [18F]FE-PE2I PET were compared between the participants carrying one or two 9-repeat alleles (i.e. 9R+10R or 9R+9R; 47%) and the participants without a 9R allele (i.e. 10R+10R or 10R+11R; 53%). Nonparametric tests, linear regression analysis and mixed model analysis were used to assess any statistical difference in measured DAT availability between the two allele groups.

    RESULTS: The measured DAT-availability in PET- and SPECT-imaging tended to be slightly higher in the 9R-group; however, the difference did not reach statistical significance in either the caudate or the putamen or the substantia nigra. Instead, age did have a significant effect on the DAT level (P < 0.05) notwithstanding the genotype.

    CONCLUSION: No significant effect of DAT1-genotype was detectable in imaging with [18F]FE-PE2I PET or [123I]FP-Cit, instead, age accounted for the normal variation in DAT-PET and DAT-SPECT.

  • 2.
    Jonsson, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Burstedt, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa2018Ingår i: Molecular Vision, ISSN 1090-0535, Vol. 24, s. 667-678Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Retinitis pigmentosa (RP) represents a large group of inherited retinal diseases characterized by clinical and genetic heterogeneity. Among patients with RP in northern Sweden, we identified two severely affected siblings and aimed to reveal a genetic cause underlying their disease.

    Methods: Whole exome sequencing (WES) was performed on both affected individuals. Sequence variants were filtered using a custom pipeline to find a rare or novel variant predicted to affect protein function. Genome-wide genotyping was used to identify copy number variants (CNVs) and homozygous regions with potential disease causative genes.

    Results: WES uncovered a novel heterozygous variant in the MER proto-oncogene, tyrosine kinase (MERTK) gene, c.2309A>G, p.Glu770Gly located in the tyrosine kinase domain and predicted to be likely pathogenic. The second variant, a large heterozygous deletion encompassing exons 1 to 7 of the MERTK gene, was revealed with genome-wide genotyping. The CNV analysis suggested breakpoints of the deletion, in the 5′-untranslated region and in intron 7. We identified genomic sequences at the site of the deletion as part of L1ME4b (LINE/L1) and AluSx3 that indicated a non-homologous recombination as a mechanism of the deletion evolvement.

    Conclusions: Patients with RP in this study were carriers of two novel allelic mutations in the MERTK gene, a missense variant in exon 17 and an approximate 91 kb genomic deletion. Mapping of the deletion breakpoints allowed molecular testing of a cohort of patients with RP with allele-specific PCR. These findings provide additional information about mutations in MERTK for molecular testing of unsolved recessive RP cases and highlight the necessity for analysis of large genomic deletions.

  • 3.
    Jonsson, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Byström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sandgren, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 4, s. 463-473Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 4.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Hidden patterns that matter: statistical methods for analysis of DNA and RNA data2020Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Understanding how the genetic variations can affect characteristics and function of organisms can help researchers and medical doctors to detect genetic alterations that cause disease and reveal genes that causes antibiotic resistance. The opportunities and progress associated with such data come however with challenges related to statistical analysis. It is only by using properly designed and employed tools, that we can extract the information about hidden patterns. In this thesis we present three types of such analysis. First, the genetic variant in the gene COL17A1 that causes corneal dystrophy with recurrent erosions is reveled. By studying Next-generation sequencing data, the order of the nucleotides in the DNAsequence was be obtained, which enabled us to detect interesting variants in the genome. Further, we present results of an experimental design study with the aim to make the best selection from a family that is affected by an inherited disease. In second part of the work, we analyzed a novel antibiotic resistance Staphylococcus epidermidis clone that is only found in northern Europe. By investigating its genetic data, we revealed similarities to a world known antibiotic resistance clone. As a result, the antibiotic resistance profile is established from the DNA sequences. Finally, we also focus on the challenges related to the abundance of genetic data from different sources. The increasing number of public gene expression datasets gives us opportunity to increase our understanding by using information from multiple sources simultaneously. Naturally, this requires merging independent datasets together. However, when doing so, the technical and biological variation in the joined data increases. We present a pre-processing method to construct gene co-expression networks from a large diverse gene-expression dataset.

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  • 5.
    Kellgren, Therese
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Dwibedi, Chinmay Kumar
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Widerström, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Monsen, Tor J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    The emergence of an antimicrobial resistant Staphylococcus epidermidis clone in Northern EuropeManuskript (preprint) (Övrigt vetenskapligt)
  • 6.
    Kellgren, Therese
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Experimental designs for finding disease-causing mutations in rare diseasesManuskript (preprint) (Övrigt vetenskapligt)
  • 7.
    Law, Simon R
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Björk, Rafael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keech, Olivier
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Centralization Within Sub-Experiments Enhances the Biological Relevance of Gene Co-expression Networks: A Plant Mitochondrial Case Study2020Ingår i: Frontiers in Plant Science, E-ISSN 1664-462X, Vol. 11, artikel-id 524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gene co-expression networks (GCNs) can be prepared using a variety of mathematical approaches based on data sampled across diverse developmental processes, tissue types, pathologies, mutant backgrounds, and stress conditions. These networks are used to identify genes with similar expression dynamics but are prone to introducing false-positive and false-negative relationships, especially in the instance of large and heterogenous datasets. With the aim of optimizing the relevance of edges in GCNs and enhancing global biological insight, we propose a novel approach that involves a data-centering step performed simultaneously per gene and per sub-experiment, called centralization within sub-experiments (CSE). Using a gene set encoding the plant mitochondrial proteome as a case study, our results show that all CSE-based GCNs assessed had significantly more edges within the majority of the considered functional sub-networks, such as the mitochondrial electron transport chain and its complexes, than GCNs not using CSE; thus demonstrating that CSE-based GCNs are efficient at predicting canonical functions and associated pathways, here referred to as the core gene network. Furthermore, we show that correlation analyses using CSE-processed data can be used to fine-tune prediction of the function of uncharacterized genes; while its use in combination with analyses based on non-CSE data can augment conventional stress analyses with the innate connections underpinning the dynamic system being examined. Therefore, CSE is an effective alternative method to conventional batch correction approaches, particularly when dealing with large and heterogenous datasets. The method is easy to implement into a pre-existing GCN analysis pipeline and can provide enhanced biological relevance to conventional GCNs by allowing users to delineate a core gene network. Author Summary Gene co-expression networks (GCNs) are the product of a variety of mathematical approaches that identify causal relationships in gene expression dynamics but are prone to the misdiagnoses of false-positives and false-negatives, especially in the instance of large and heterogenous datasets. In light of the burgeoning output of next-generation sequencing projects performed on a variety of species, and developmental or clinical conditions; the statistical power and complexity of these networks will undoubtedly increase, while their biological relevance will be fiercely challenged. Here, we propose a novel approach to generate a "core" GCN with enhanced biological relevance. Our method involves a data-centering step that effectively removes all primary treatment/tissue effects, which is simple to employ and can be easily implemented into pre-existing GCN analysis pipelines. The gain in biological relevance resulting from the adoption of this approach was assessed using a plant mitochondrial case study.

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  • 8.
    Li, Xingru
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ling, Agnes
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kellgren, Therese G.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Löfgren Burström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rutegård, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Edin, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 11, artikel-id 3440Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.

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  • 9.
    Löwenmark, Thyra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Li, Xingru
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Löfgren Burström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ling, Agnes
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kellgren, Therese G.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Edin, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer2022Ingår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 71, s. 2565-2575Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The importance of the tumour microbiome in different aspects of colorectal cancer (CRC) has been increasingly recognised, but many questions remain. The aim of this study was to explore the effect of specific CRC associated microbes on the tumour immune response, which has a considerable prognostic value in CRC. We applied specific qPCR to detect Parvimonas micra and Fusobacterium nucleatum in tumour tissues from an immunologically well-characterised cohort of 69 CRC patients. This cohort included detailed analyses of immune profiles based on flow cytometry and transcriptomics in tumour tissue and blood, along with comprehensive analyses of molecular subtypes. P. micra and F. nucleatum were detected in 24% and 64% of tumour tissues, respectively. We found a significant association of P. micra with high-grade tumours and tumours of CMS1 subtype. F. nucleatum was significantly associated with right-sided tumours, microsatellite instability, and CMS1 tumours. The immunological analyses revealed significant associations of P. micra with activated CD69+ T lymphocytes and increased antigen-presenting HLA-DR+ B lymphocytes. P. micra was also positively associated with M1 and M2 macrophage traits. The impact of P. micra tumour colonisation on the immune response was further assessed using transcriptomics in validation of our findings. No associations were found between F. nucleatum and immune profiles in this study. Our findings support novel associations between P. micra and the immune response in CRC. A better understanding of these interactions might help to identify important predictive and prognostic tools as well as new targets for therapy.

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  • 10.
    Stattin, Eva-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Henning, Petra
    Klar, Joakim
    McDermott, Emma
    Stecksen-Blicks, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Sandström, Per-Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Kellgren, Therese G
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Lönnerholm, Torsten
    Ameur, Adam
    Helfrich, Miep H
    Coxon, Fraser P
    Dahl, Niklas
    Wikström, Johan
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts2017Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikel-id 3012Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

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