| 1. |
- Lill, Christina M., et al.
(författare)
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Closing the case of APOE in multiple sclerosis : no association with disease risk in over 29 000 subjects
- 2012
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:9, s. 558-562
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Tidskriftsartikel (refereegranskat)abstract
- Background Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently.Methods We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments.Results Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively).Conclusion Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
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| 2. |
- Wessels, Kathrin, et al.
(författare)
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Novel CHD7 mutations contributing to the mutation spectrum in patients with CHARGE syndrome
- 2010
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Ingår i: EUROPEAN JOURNAL OF MEDICAL GENETICS. - : Elsevier Science B.V., Amsterdam. - 1769-7212. ; 53:5, s. 280-285
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Tidskriftsartikel (refereegranskat)abstract
- CHARGE syndrome is an autosomal dominant inherited multiple malformation disorder typically characterized by coloboma, choanal atresia, hypoplastic semicircular canal, cranial nerve defects, cardiovascular malformations and ear abnormalities. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are the major cause of CHARGE syndrome. Mutation analysis was performed in 18 patients with firm or tentative clinical diagnosis of CHARGE syndrome. In this study eight mutations distributed across the gene were found. Five novel mutations - one missense (c.2936Tandgt;C), one nonsense (c.8093Candgt;A) and three frameshift mutations (c.804_805insAT, c.1757_1770del14, c.1793delA) - were identified. As far as familial data were available these mutations were found to have arisen de novo. Comparison of the clinical features of patients with the same mutation demonstrates that expression of the phenotype is highly variable. The mutation detection rate in this study was 44.4% in patients with a clinically established or suspected diagnosis of CHARGE syndrome.
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| 3. |
- Reinthaler, Eva M., et al.
(författare)
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TPP2 mutation associated with sterile brain inflammation mimicking MS
- 2018
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Ingår i: NEUROLOGY-GENETICS. - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective To ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS.Methods We used homozygosity mapping and next-generation sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted sequencing of further MS cases from Austria, Germany, Canada and Jordan.Results In this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II (TPP2) gene in all 3 affected siblings of the family. Sequencing of all TPP2-coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without TPP2 mutations was highly upregulated.Conclusions The homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. TPP2 is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in TPP2 were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that TPP2 may play a broader role in the inflammatory process in MS.
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