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| 2. |
- Chiang, Huei-Hsin
(author)
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Genetic characterization of patients with frontotemporal dementia and amyotrophic lateral sclerosis in the Nordic countries
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Frontotemporal dementia (FTD) is the second most common form of neurodegenerative disease affecting people under the age of 65 years. The general symptoms are dysfunctions in behavior and/or language. Up to 50 % of FTD patients have a positive family history for dementia and mutations in the progranulin (GRN) gene account for 13-25 % of the familial cases. In Paper I, the Swedish Karolinska family with FTD was shown to have a GRN mutation, p.Gly35GlufsX19, which segregated with the disease. The mutation resulted in an ~50 % reduction of the GRN transcript. Sequencing the GRN cDNA resulted in only wild type sequence indicating that the mutant allele had been degraded resulting in reduced GRN transcript levels. GRN mutations have reduced penetrance which is shown e.g. in the Karolinska family where there is a 10 years range in age at onset. The single nucleotide polymorphism (SNP) rs1990622, in linkage disequilibrium with the transmembrane protein 106B (TMEM106B) gene, was suggested to modify age at onset in GRN mutations carriers. In Paper II, the effect of rs1990622 on age at onset in four GRN mutation families, including the Karolinska family was investigated. Patients homozygous for the A allele were shown to have a significantly earlier (13 years) median age at onset compared to patients with the GA or GG genotype. To investigate possible disease mechanisms of rs1990622, the GRN levels in plasma and the TMEM106B mRNA levels in brain tissue were measured. An effect of rs1990622 genotype on plasma-GRN levels was detected with AA carriers having the lowest GRN levels and GG carriers the highest levels. However, this effect was not shown to be mediated by the modulation of TMEM106B transcript levels. In Paper III, 100 FTD patients from Sweden were screened for GRN mutations and four premature stop codon mutations were identified: p.Gly35GlufsX19, p.Cys416LeufsX30, p.Tyr294X and p.Cys404X. Furthermore, the p. Cys416LeufsX30 was shown to segregate in a family with clinical heterogeneity. The serum-GRN levels in carriers of the three first premature stop codons showed a more than 50 % reduction compared to non-carriers. GRN levels and age at onset in the patient cohort varied and were thus investigated for association with rs1990622, rs5848 (located in the 3’UTR of GRN) and apolipoprotein E (APOE). Patients with the TT genotype at rs5848 had significantly lower GRN levels compared to CT and CC genotypes. Moreover, APOE ɛ4 positive patients had a significantly later age at onset compared to ɛ4 negative patients. FTD and amyotrophic lateral sclerosis (ALS) are part of the same disease spectrum. The identification of TAR DNA binding protein 43 (TDP-43) positive neuronal inclusions in the majority of ALS and FTD patients further supported the link. To investigate the importance of TARDBP (the gene encoding TDP-43) mutations in Nordic ALS patients, 177 patients were sequenced in Paper IV. Four missense variations in three familial ALS patients were detected: p.Ala90Val, p.Gly357Arg, p.Arg361Thr and p.Ser379Pro. The three last missense variations were concluded to be possibly pathogenic since they were predicted by in silico analysis to be pathogenic and were absent in 200 neurologically healthy controls. The mutation frequency of TARDBP in Nordic ALS patient was 1.7 %. Furthermore, the p.Arg361Thr was shown to be present in a family with both ALS and FTD-ALS which further strengthens the connection between FTD and ALS.
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- Chiang, Huei-Hsin, et al.
(author)
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Novel TARDBP mutations in Nordic ALS patients
- 2012
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In: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 57:5, s. 316-319
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.
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| 4. |
- Ferrari, Raffaele, et al.
(author)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
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In: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 5. |
- Keller, Lina, et al.
(author)
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The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of A beta in different brain regions
- 2010
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In: European Journal of Human Genetics. - London : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 18:11, s. 1202-1208
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Journal article (peer-reviewed)abstract
- Early-onset dominantly inherited forms of Alzheimer's disease (AD) are rare, but studies of such cases have revealed important information about the disease mechanisms. Importantly, mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and PSEN2, alter the APP processing and lead to an increased amyloid beta-peptide (A beta) 42/40 ratio. This, together with other studies on pathogenic mechanisms, show that A beta 42 is a major player in the etiology of AD. Here, we present a clinical and neuropathological description of a Swedish family with an I143T mutation in the PSEN1 gene, which gives rise to a severe form of AD. We also performed an extensive investigation on the concentration and distribution of A beta species of different lengths in six brain regions from two mutation carriers. Our study showed that A beta 42 and a longer peptide, A beta 43, were present both in plaque cores and in total amyloid preparations, and were each clearly more frequent than A beta 40 in all examined regions, as shown by both mass spectrometry and immunohistochemistry. European Journal of Human Genetics (2010) 18, 1202-1208; doi: 10.1038/ejhg.2010.107; published online 14 July 2010
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