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Nordin, Frida
Publications (6 of 6) Show all publications
Müller, K., Oh, K.-W., Nordin, A., Panthi, S., Kim, S. H., Nordin, F., . . . Andersen, P. M. (2022). De novo mutations in SOD1 are a cause of ALS. Journal of Neurology, Neurosurgery and Psychiatry, 93, 201-206
Open this publication in new window or tab >>De novo mutations in SOD1 are a cause of ALS
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2022 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 93, p. 201-206Article in journal (Refereed) Published
Abstract [en]

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.

Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.

Results: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.

Conclusions:  De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.

Data availability statement: Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2022
Keywords
Psychiatry and Mental health, Clinical Neurology, Surgery
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-189488 (URN)10.1136/jnnp-2021-327520 (DOI)000722681900001 ()2-s2.0-85120353083 (Scopus ID)
Funder
Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseSwedish Association of Persons with Neurological DisabilitiesKnut and Alice Wallenberg Foundation, 2012.0091, 2014.0305, 2020.0232The Swedish Brain Foundation, 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2020-0353Swedish Research Council, 2012-3167, 2017-03100Region Västerbotten
Available from: 2021-11-12 Created: 2021-11-12 Last updated: 2023-03-24Bibliographically approved
Oeckl, P., Weydt, P., Steinacker, P., Anderl-Straub, S., Nordin, F., Volk, A. E., . . . Otto, M. (2019). Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase. Journal of Neurology, Neurosurgery and Psychiatry, 90(1), 4-10
Open this publication in new window or tab >>Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase
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2019 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 1, p. 4-10Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.

Methods: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.

Results: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).

Conclusion: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-157233 (URN)10.1136/jnnp-2018-318868 (DOI)000459181800004 ()30224549 (PubMedID)2-s2.0-85053665746 (Scopus ID)
Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2023-03-24Bibliographically approved
Nordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Forsberg, K., Baumann, P., . . . Andersen, P. M. (2017). Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 18(3-4), 256-264
Open this publication in new window or tab >>Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study
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2017 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 3-4, p. 256-264Article in journal (Refereed) Published
Abstract [en]

A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele. In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.

Keywords
ALS, C9orf72, FTD, RP-PCR interpretation, variants
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-134981 (URN)10.1080/21678421.2016.1262423 (DOI)000400792800012 ()27936955 (PubMedID)2-s2.0-85003794482 (Scopus ID)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2023-03-23Bibliographically approved
Ohta, Y., Soucy, G., Phaneuf, D., Audet, J.-N., Gros-Louis, F., Rouleau, G. A., . . . Julien, J.-P. (2016). Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis. Human Molecular Genetics, 25(21), 4771-4786
Open this publication in new window or tab >>Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis
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2016 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 21, p. 4771-4786Article in journal (Refereed) Published
Abstract [en]

Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2016
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-134285 (URN)10.1093/hmg/ddw304 (DOI)000397061300013 ()28175304 (PubMedID)2-s2.0-85014869421 (Scopus ID)
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2023-03-24Bibliographically approved
Freischmidt, A., Wieland, T., Richter, B., Ruf, W., Schaeffer, V., Mueller, K., . . . Weishaupt, J. H. (2015). Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nature Neuroscience, 18(5), 631-+
Open this publication in new window or tab >>Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
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2015 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 18, no 5, p. 631-+Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-103728 (URN)10.1038/nn.4000 (DOI)000353636900009 ()25803835 (PubMedID)2-s2.0-84928695187 (Scopus ID)
Available from: 2015-06-09 Created: 2015-05-28 Last updated: 2023-03-24Bibliographically approved
Forsgren, E., Nordin, F., Nordström, U., Rofougaran, R., Danielsson, J., Marklund, S., . . . Andersen, P.A Novel mutation D96Mfs*8 in SOD1 identified in a Swedish ALS patient results in a truncated and heavily aggregation-prone protein.
Open this publication in new window or tab >>A Novel mutation D96Mfs*8 in SOD1 identified in a Swedish ALS patient results in a truncated and heavily aggregation-prone protein
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(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Keywords
Amyotrophic lateral sclerosis, superoxide dismutase, mutation, SOD1 aggregation
National Category
Natural Sciences
Identifiers
urn:nbn:se:umu:diva-138945 (URN)
Available from: 2017-09-04 Created: 2017-09-04 Last updated: 2019-11-19
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