| 1. |
|
|
| 2. |
|
|
| 3. |
- Springer, W, et al.
(författare)
-
Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
-
Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
-
Konferensbidrag (refereegranskat)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
|
|
| 4. |
- Wang, Y. X., et al.
(författare)
-
Diagnostic potential of tumor DNA from ovarian cyst fluid
- 2016
-
Ingår i: Elife. - 2050-084X. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- We determined whether the mutations found in ovarian cancers could be identified in the patients' ovarian cyst fluids. Tumor-specific mutations were detectable in the cyst fluids of 19 of 23 (83%) borderline tumors, 10 of 13 (77%) type I cancers, and 18 of 18 (100%) type II cancers. In contrast, no mutations were found in the cyst fluids of 18 patients with benign tumors or nonneoplastic cysts. Though large, prospective studies are needed to demonstrate the safety and clinical utility of this approach, our results suggest that the genetic evaluation of cyst fluids might be able to inform the management of the large number of women with these lesions.
|
|
| 5. |
- Westerman, Michael, et al.
(författare)
-
Phylogenetic relationships of dasyuromorphian marsupials revisited
- 2016
-
Ingår i: Zoological Journal of the Linnean Society. - : Oxford University Press (OUP). - 0024-4082 .- 1096-3642. ; 176:3, s. 686-701
-
Tidskriftsartikel (refereegranskat)abstract
- We reassessed the phylogenetic relationships of dasyuromorphians using a large molecular database comprising previously published and new sequences for both nuclear (nDNA) and mitochondrial (mtDNA) genes from the numbat (Myrmecobius fasciatus), most living species of Dasyuridae, and the recently extinct marsupial wolf, Thylacinus cynocephalus. Our molecular tree suggests that Thylacinidae is sister to Myrmecobiidae+Dasyuridae. We show robust support for the dasyurid intrafamilial classification proposed by Krajewski & Westerman as well as for placement of most dasyurid genera, which suggests substantial homoplasy amongst craniodental characters presently used to generate morphology-based taxonomies. Molecular dating with relaxed molecular clocks suggests that dasyuromorphian cladogenesis began in the Eocene, and that all three dasyuromorphian families originated prior to the end of this epoch. Radiation within Thylacinidae and Dasyuridae had occurred by the middle to late Oligocene, consistent with recognition of primitive thylacinids (e.g. Badjcinus turnbulli) in the later Oligocene and of putative dasyurids (e.g. Barinya wangala) by the early Miocene. We propose that all four extant dasyurid tribes were in existence by the early Miocene and that most modern dasyurid genera/species were established before the later Miocene. This is in marked contrast to the popularly accepted advocation of their origins in the latest Miocene-early Pliocene.
|
|
