Idiopathic Parkinson's disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate ...the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible.
The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls.
To screen >1000 patients with movement disorders for rare ...ANO3 variants.
We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis.
Nine carriers (seven with dystonia 1.0%, two with PD 0.7%) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation.
This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.
•Large scale (>1000 patients) screening study for ANO3 mutations.•Identification of recurrent ANO3 variants supporting pathogenicity.•Identification of a de novo ANO3 variant supporting pathogenicity.•Good response to deep brain stimulation in the patient with the de-novo variant.
Summary Background DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1 dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region. Recently, two ...mutations in THAP1 , the gene that encodes THAP (thanatos-associated protein) domain-containing apoptosis-associated protein 1 (THAP1), have been identified as a cause of DYT6 dystonia. Methods We screened THAP1 by sequence analysis and quantitative real-time polymerase chain reaction (PCR) in 160 white patients of European ancestry who had dystonia with an early age at onset (n=64), generalised dystonia (n=35), a positive family history of dystonia (n=56), or facial or laryngeal dystonia. Another 160 patients with dystonia were screened for reported and novel variants in THAP1 . 280 neurologically healthy controls were screened for the newly identified and previously reported changes in THAP1 and these and an additional 75 controls were screened for a rare non-coding mutation. Findings We identified two mutations in THAP1 (388_389delTC and 474delA), respectively, in two (1%) German patients from the 160 patients with dystonia. Both mutation carriers had laryngeal dystonia that started in childhood and both went on to develop generalised dystonia. Thus, two of three patients with early-onset generalised dystonia with orobulbar involvement had mutations in THAP1 . One of the identified patients with DYT6 dystonia had two family members with subtle motor signs who also carried the same mutation. A rare substitution in the 5′untranslated region (−236_235GA→TT) was found in 20 of 320 patients and in seven of 355 controls (p=0·0054). Interpretation Although mutations in THAP1 might have only a minor role in patients with different, but mainly focal, forms of dystonia, they do seem to be associated with early-onset generalised dystonia with spasmodic dysphonia. This combination of symptoms might be a characteristic feature of DYT6 dystonia and could be useful in the differential diagnosis of DYT1, DYT4, DYT12 , and DYT17 dystonia. In addition to the identified mutations, a rare non-coding substitution in THAP1 might increase the risk of dystonia. Funding Deutsche Forschungsgemeinschaft; Volkswagen Foundation; Dystonia Medical Research Foundation; University of Lübeck.
Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) cause a form of early-onset, isolated dystonia (DYT-THAP1, aka DYT6). Here, we describe the generation of eight human ...induced pluripotent stem cell (iPSC) lines of manifesting and non-manifesting carriers of the THAP1 mutations p.Lys158Asnfs*23 or p.Arg13His (each 4 lines). Dermal fibroblasts were reprogrammed using non-integrating Sendai virus. The iPSC lines were comprehensively characterized including expression analyses of pluripotency markers, the potential to differentiate into cells of all three germ layers, and stable karyotypes. These lines provide a valuable resource for studying the impact of THAP1 mutations on the pathology of dystonia.
Despite being a major component of Lewy bodies and Lewy neurites, pathogenic variants in the gene encoding alpha-Synuclein (α-Syn) are rare. To date, only four missense variants in the SNCA gene, ...encoding α-Syn have unequivocally been shown to be disease-causing. We here describe a Parkinson´s disease patient with early cognitive decline carrying an as yet not fully characterized variant in SNCA (NM_001146055: c.44T > C, p.V15A). We used different cellular models, including stably transfected neuroblastoma (SH-SY5Y) cell cultures, induced pluripotent stem cell (iPSC)-derived neuronal cultures, and generated a Drosophila model to elucidate the impact of the p.V15A variant on α-Syn function and aggregation properties compared to other known pathogenic variants. We demonstrate that p.V15A increased the aggregation potential of α-Syn and the levels of apoptotic markers, and impaired the mitochondrial network. Moreover, p.V15A affects the flying ability and survival of mutant flies. Thus, we provide supporting evidence for the pathogenicity of the p.V15A variant, suggesting its inclusion in genetic testing approaches.
This study evaluates the impact of atmospheric horizontal resolution on the
representation of cloud radiative effects (CREs) in an ensemble of global
climate model simulations following the protocols ...of the High Resolution
Model Intercomparison Project (HighResMIP). We compare results from four
European modelling centres, each of which provides data from “standard”-
and “high”-resolution model configurations. Simulated radiative fluxes are
compared with observation-based estimates derived from the Clouds and Earth's
Radiant Energy System (CERES) dataset. Model CRE biases are evaluated using
both conventional statistics (e.g. time and spatial averages) and after
conditioning on the phase of two modes of internal climate variability,
namely the El Niño–Southern Oscillation (ENSO) and the North Atlantic
Oscillation (NAO). Simulated top-of-atmosphere (TOA) and surface CREs show
large biases over the polar regions, particularly over regions where seasonal
sea-ice variability is strongest. Increasing atmospheric resolution does not
significantly improve these biases. The spatial structure of the cloud
radiative response to ENSO and NAO variability is simulated reasonably well
by all model configurations considered in this study. However, it is
difficult to identify a systematic impact of atmospheric resolution on the
associated CRE errors. Mean absolute CRE errors conditioned on the ENSO phase
are relatively large (5–10 W m−2) and show differences between
models. We suggest this is a consequence of differences in the
parameterization of SW radiative transfer and the treatment of cloud optical
properties rather than a result of differences in resolution. In contrast,
mean absolute CRE errors conditioned on the NAO phase are generally smaller
(0–2 W m−2) and more similar across models. Although the regional
details of CRE biases show some sensitivity to atmospheric resolution within
a particular model, it is difficult to identify patterns that hold across all
models. This apparent insensitivity to increased atmospheric horizontal
resolution indicates that physical parameterizations play a dominant role in
determining the behaviour of cloud–radiation feedbacks. However, we note
that these results are obtained from atmosphere-only simulations and the
impact of changes in atmospheric resolution may be different in the presence
of coupled climate feedbacks.
Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (
) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor-parkinsonism ...syndrome. Here, we describe four new patients, who all presented at a young age with a tremor-parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported
-related disorders. In conclusion,
-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.
PDF
