| 51. |
- Bomprezzi, R, et al.
(författare)
-
Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease
- 2003
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 12:17, s. 2191-2199
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) and other T cell-mediated autoimmune diseases develop in individuals carrying a complex susceptibility trait, probably following exposure to various environmental triggers. Owing to the presumed weak influence of single genes on disease predisposition and the recognized genetic heterogeneity of autoimmune disorders in humans, candidate gene searches in MS have been difficult. In an attempt to identify molecular markers indicative of disease status rather than susceptibility genes for MS, we show that gene expression profiling of peripheral blood mononuclear cells by cDNA microarrays can distinguish MS patients from healthy controls. Our findings support the concept that the activation of autoreactive T cells is of primary importance for this complex organ-specific disorder and prompt further investigations on gene expression in peripheral blood cells aimed at characterizing disease phenotypes.
|
|
| 52. |
- Bondeson, Marie-Louise, et al.
(författare)
-
Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome
- 1995
-
Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 4:4, s. 615-621
-
Tidskriftsartikel (refereegranskat)abstract
- We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.
|
|
| 53. |
- Borné, Yan, et al.
(författare)
-
Genome wide association study identifies two loci associated with cadmium in erythrocytes among never-smokers
- 2016
-
Ingår i: Hum Mol Genet. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:11, s. 2342-2348
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Cadmium is a non-essential toxic metal with multiple adverse health effects. Exposure in the general population occurs by smoking and diet. Cadmium in erythrocytes is a valid biomarker of exposure and body burden of cadmium. Objectives: We aimed to identify genetic variants related to concentrations of cadmium in erythrocytes. Methods: Erythrocyte cadmium was analyzed in 4432 individuals (1728 never smokers) from the Swedish population-based Malmo Diet and Cancer cohort. Genotyping was performed using the Illumina HumanOmniExpressExome Bead chip with genome-wide coverage. Genome wide analyses were performed in the whole sample and in never smokers. Results: No single nucleotide polymorphism (SNP) reached a genome-wide significant association with erythrocyte cadmium in the whole sample. However, in never smokers, 14 variants showed genome-wide significant relationships with erythrocyte cadmium after adjusting for age and sex. Thirteen variants were in linkage disequilibrium on chromosome 8q13.3 in the XKR9 and LACTB2 genes. The lead SNP on 8q13.3 was rs12681420 (minor allele G, minor allele frequency [MAF] = 0.46, beta: -0.11, P = 3.48 x 10(-11)), an intron variant within the XKR9 gene. The other significant locus, rs17574271 (minor allele C, MAF = 0.09, beta: 0.17, P = 6.18 x 10(-9)), was an intron variant within the DLGAP1 gene at chromosome 18p11.31. Conclusion: This genome-wide study of never smokers from the general population identified two independent regions related to erythrocyte cadmium. The strongest locus covers the XKR9 and LACTB2 genes, which both could have related functions in cadmium absorption and metabolism. Replication studies are needed to confirm the findings and mechanisms should be further investigated.
|
|
| 54. |
- Bossini-Castillo, Lara, et al.
(författare)
-
A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations
- 2012
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:4, s. 926-933
-
Tidskriftsartikel (refereegranskat)abstract
- A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P-MH = 1.92 x 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P-MH = 4.84 x 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P-chi 2 = 2.82 x 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P-MH = 2.82 x 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
|
|
| 55. |
|
|
| 56. |
|
|
| 57. |
|
|
| 58. |
- Bras, Jose, et al.
(författare)
-
Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
- 2014
-
Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 23:23, s. 6139-6146
-
Tidskriftsartikel (refereegranskat)abstract
- Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
|
|
| 59. |
- Braun, Sebastian, et al.
(författare)
-
Pharmacological interference with the glucocorticoid system influences symptoms and lifespan in a mouse model of Rett syndrome.
- 2012
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:8, s. 1673-1680
-
Tidskriftsartikel (refereegranskat)abstract
- Rett syndrome (RTT) is caused by loss-of-function mutations in the X-linked gene MECP2 coding for methyl CpG-binding protein 2 (MeCP2). This protein can act as transcriptional repressor and we showed in a previous study that glucocorticoid-inducible genes are up-regulated in a RTT mouse model and that these genes are direct MeCP2 targets. Here, we report that pharmacological intervention with the glucocorticoid system has an impact on the symptoms and lifespan in a RTT mouse model. Our data support a functional implication of the stress hormone system in RTT and suggest this hormone system as potential therapeutic target.
|
|
| 60. |
- Braunstein, Kerstin E., et al.
(författare)
-
A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons
- 2010
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:22, s. 4385-4398
-
Tidskriftsartikel (refereegranskat)abstract
- The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.
|
|
