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Norberg, Anna
Publications (10 of 15) Show all publications
Carlund, O., Norberg, A., Osterman, P., Landfors, M., Degerman, S. & Hultdin, M. (2023). DNA methylation variations and epigenetic aging in telomere biology disorders. Scientific Reports, 13(1), Article ID 7955.
Open this publication in new window or tab >>DNA methylation variations and epigenetic aging in telomere biology disorders
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2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 7955Article in journal (Refereed) Published
Abstract [en]

Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-209273 (URN)10.1038/s41598-023-34922-1 (DOI)000992335400030 ()37193737 (PubMedID)2-s2.0-85159474361 (Scopus ID)
Funder
The Kempe FoundationsCancerforskningsfonden i NorrlandUmeå UniversityRegion Västerbotten
Available from: 2023-06-08 Created: 2023-06-08 Last updated: 2023-09-05Bibliographically approved
Norén-Nyström, U., Andersen, M. K., Barbany, G., Dirse, V., Eilert-Olsen, M., Engvall, M., . . . Johansson, B. (2023). Genetic subtypes and outcome of patients aged 1 to 45 years old with acute lymphoblastic leukemia in the NOPHO ALL2008 trial [Letter to the editor]. HemaSphere, 7(5), Article ID E883.
Open this publication in new window or tab >>Genetic subtypes and outcome of patients aged 1 to 45 years old with acute lymphoblastic leukemia in the NOPHO ALL2008 trial
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2023 (English)In: HemaSphere, E-ISSN 2572-9241, Vol. 7, no 5, article id E883Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Wolters Kluwer, 2023
National Category
Hematology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-209280 (URN)10.1097/HS9.0000000000000883 (DOI)000982272500002 ()2-s2.0-85159277173 (Scopus ID)
Available from: 2023-06-08 Created: 2023-06-08 Last updated: 2023-09-05Bibliographically approved
Bergstrand, S., Böhm, S., Malmgren, H., Norberg, A., Sundin, M., Nordgren, A. & Farnebo, M. (2020). Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome. Cell Death and Disease, 11(4), Article ID 238.
Open this publication in new window or tab >>Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome
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2020 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 11, no 4, article id 238Article in journal (Refereed) Published
Abstract [en]

Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53 beta (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53 beta, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53 beta HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53 beta-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-170826 (URN)10.1038/s41419-020-2421-4 (DOI)000528732700007 ()32303682 (PubMedID)2-s2.0-85083805510 (Scopus ID)
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilRegion StockholmThe Swedish Brain Foundation
Available from: 2020-05-25 Created: 2020-05-25 Last updated: 2023-03-23Bibliographically approved
Olsson-Arvidsson, L., Norberg, A., Sjögren, H. & Johansson, B. (2020). Frequent false-negative FIP1L1-PDGFRA FISH analyses of bone marrow samples from clonal eosinophilia at diagnosis [Letter to the editor]. British Journal of Haematology, 188(5), e64-e79
Open this publication in new window or tab >>Frequent false-negative FIP1L1-PDGFRA FISH analyses of bone marrow samples from clonal eosinophilia at diagnosis
2020 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, no 5, p. e64-e79Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2020
Keywords
clonal eosinophilia, fluorescence in situ hybridisation, routine diagnostics, false negativity
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-167093 (URN)10.1111/bjh.16340 (DOI)000503358200001 ()31854104 (PubMedID)2-s2.0-85076725908 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2017/291Swedish Research Council, 2016-01084
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2023-03-24Bibliographically approved
Hirvonen, E. A. M., Peuhkuri, S., Norberg, A., Degerman, S., Hannula-Jouppi, K., Välimaa, H., . . . Wartiovaara-Kautto, U. (2019). Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation. Leukemia, 33(1), 275-278
Open this publication in new window or tab >>Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 1, p. 275-278Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155772 (URN)10.1038/s41375-018-0243-5 (DOI)000455200900028 ()30185935 (PubMedID)2-s2.0-85053378239 (Scopus ID)
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2023-03-23Bibliographically approved
Trotta, L., Norberg, A., Taskinen, M., Beziat, V., Degerman, S., Wartiovaara-Kautto, U., . . . Martelius, T. (2018). Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders. Orphanet Journal of Rare Diseases, 13, Article ID 139.
Open this publication in new window or tab >>Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders
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2018 (English)In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 13, article id 139Article in journal (Refereed) Published
Abstract [en]

Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKQ, the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.

Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.

Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.

Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2018
Keywords
telomere biology disorders, telomeropathies, next-generation sequencing, whole-exome quencing, dyskeratosis congenita, DKC1, TERT, RTEL1
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-151557 (URN)10.1186/s13023-018-0864-9 (DOI)000442134700001 ()30115091 (PubMedID)2-s2.0-85051726365 (Scopus ID)
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2024-03-14Bibliographically approved
Norberg, A., Rosén, A., Raaschou-Jensen, K., Kjeldsen, L., Moilanen, J. S., Paulsson-Karisson, Y., . . . Hultdin, M. (2018). Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. European Journal of Human Genetics, 26(6), 858-867
Open this publication in new window or tab >>Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
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2018 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed) Published
Abstract [en]

Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-149013 (URN)10.1038/s41431-018-0112-8 (DOI)000433424200010 ()29483670 (PubMedID)2-s2.0-85042538231 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Winbo, A., Stattin, E.-L., Westin, I. M., Norberg, A., Persson, J., Jensen, S. M. & Rydberg, A. (2017). Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis. BMC Medical Genetics, 18, Article ID 74.
Open this publication in new window or tab >>Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis
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2017 (English)In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 18, article id 74Article in journal (Refereed) Published
Abstract [en]

Background: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1APsequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations.

Methods: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs.

Results: A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males.

Conclusions: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.

Keywords
Long QT syndrome, Sequence variants, Sex, Risk stratification, Modifier genes, QT prolongation, xsequence-variant interaction, Genotype-phenotype interactions, Founder populations
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-138033 (URN)10.1186/s12881-017-0435-2 (DOI)000405695100001 ()2-s2.0-85024845650 (Scopus ID)
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2024-01-17Bibliographically approved
Stattin, E.-L., Westin, I. M., Cederquist, K., Jonasson, J., Jonsson, B.-A., Mörner, S., . . . Wisten, A. (2016). Genetic screening in sudden cardiac death in the young can save future lives. International journal of legal medicine, 130(1), 59-66
Open this publication in new window or tab >>Genetic screening in sudden cardiac death in the young can save future lives
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2016 (English)In: International journal of legal medicine, ISSN 0937-9827, E-ISSN 1437-1596, Vol. 130, no 1, p. 59-66Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.

METHODS AND RESULTS: From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT).

CONCLUSION: Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

Keywords
Sudden unexplained death, Sudden cardiac death, Molecular autopsy, Long QT syndrome, Catecholaminergic polymorphic ventricular tachycardia
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-128555 (URN)10.1007/s00414-015-1237-8 (DOI)000368685400006 ()26228265 (PubMedID)2-s2.0-84954360690 (Scopus ID)
Available from: 2016-12-07 Created: 2016-12-07 Last updated: 2024-01-17Bibliographically approved
Ueda, Y., Calado, R. T., Norberg, A., Kajigaya, S., Roos, G., Hellstrom-Lindberg, E. & Young, N. S. (2014). A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome. BMC Medical Genetics, 15, 68
Open this publication in new window or tab >>A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome
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2014 (English)In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 15, p. 68-Article in journal (Refereed) Published
Abstract [en]

Background: Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. Case presentation: A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. Conclusion: We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.

Keywords
Myelodysplastic syndrome (MDS), Telomerase RNA component (TERC), H/ACA box, Southern blotting, Single Telomere Elongation Length Analysis (STELA), RNA fluorescence in situ hybridization (RNA FISH)
National Category
Hematology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-91275 (URN)10.1186/1471-2350-15-68 (DOI)000338265000001 ()2-s2.0-84902708860 (Scopus ID)
Available from: 2014-07-28 Created: 2014-07-28 Last updated: 2024-01-17Bibliographically approved
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