Identification of Novel and Recurrent Disease-Causing Mutations in Retinal Dystrophies Using Whole Exome Sequencing (WES): Benefits and Limitations

Inherited retinal dystrophies (IRDs) are Mendelian diseases with tremendous genetic and phenotypic heterogeneity. Identification of the underlying genetic basis of these dystrophies is therefore challenging. In this study we employed whole exome sequencing (WES) in 11 families with IRDs and identified disease-causing variants in 8 of them. Sequence analysis of about 250 IRD-associated genes revealed 3 previously reported disease-associated variants in RHO, BEST1 and RP1. We further identified 5 novel pathogenic variants in RPGRIP1 (p.Ser964Profs*37), PRPF8 (p.Tyr2334Leufs*51), CDHR1 (p.Pro133Arg and c.439-17G>A) and PRPF31 (p.Glu183_Met193dup). In addition to confirming the power of WES in genetic diagnosis of IRDs, we document challenges in data analysis and show cases where the underlying genetic causes of IRDs were missed by WES and required additional techniques. For example, the mutation c.439-17G>A in CDHR1 would be rated unlikely applying the standardWES analysis. Only transcript analysis in patient fibroblasts confirmed the pathogenic nature of this variant that affected splicing of CDHR1 by activating a cryptic splice-acceptor site. In another example, a 33-base pair duplication in PRPF31 missed by WES could be identified only via targeted analysis by Sanger sequencing. We discuss the advantages and challenges of using WES to identify mutations in heterogeneous diseases like IRDs

Asymmetric signature of glacial Antarctic intermediate water in the Central South Pacific

Southern Ocean Intermediate Waters (SOIWs) play a key role in modulating the global climate on glacial-interglacial time scales as they connect the Southern Ocean and the tropics. Despite their importance, the past evolution of the SOIWs in the central South Pacific is largely unknown due to a dearth of sedimentary archives. Here we compare Mg/Ca-temperature, stable carbon and oxygen isotope records from surface-dwelling (G. bulloides) and deep-dwelling (G. inflata) planktic foraminifera at site PS75/059-2 (54°12.9’ S, 125°25.53’ W; recovery 13.98 m; 3.613 m water depth), located north of the modern Subantarctic Front. Our study focuses on the temperature and salinity variability controlled by SOIWs, which were subducted at the Subantarctic Front during the Last Glacial Maximum (LGM; ~29–17ka BP) and the Penultimate Glacial Maximum (PGM; ~180–150ka BP). During both glacial periods conditions at the subsurface ocean were colder and fresher relative to the Holocene (<10ka) suggesting an enhanced presence of SOIWs. In spite of the comparable subsurface cooling during both glacial, the subsurface ocean during the PGM was saltier and 0.35‰ more depleted in δ13C in comparison to the LGM. Interestingly, the mean δ13C value of the PGM is comparable to the Carbon Isotope Minimum Events, which might suggests a larger contribution of “old” low δ13C deep waters to the study site during the PGM. A Latitudinal comparison of subsurface proxies suggests glacial asymmetries in the advection of SOIWs into the central Pacific, plausibly related to glacial changes in the convection depth of SOIWs at the South Antarctic Front area rather than changes in production of the SOIWs

Arbeitsmaerkte fuer Hochqualifizierte

'Ueber die Jahre hinweg sind die Arbeitsmaerkte fuer Hochqualifizierte immer wieder erheblichen Schwankungen ausgesetzt. Zeiten einer Akademikerschwemme wechseln sich ab mit Zeiten des Fachkraeftemangels. Beide Phaenomene sind volkswirtschaftlich, aber auch fuer die betroffenen Beschaeftigten und Unternehmer mit erheblichen Kosten verbunden, sei es ueber betraechtliche Fehlinvestitionen in Bildung, sei es ueber eine geringere Innovationsfaehigkeit und verminderte Wachstumschancen von Unternehmen, die ihren Bedarf an hoch qualifiziertem Personal nicht decken koennen. Das Bundesministerium fuer Bildung und Forschung hat im Rahmen der Berichterstattung zur technologischen Leistungsfaehigkeit Deutschlands den Forschungsverbund 'Arbeitsmaerkte fuer Hochqualifizierte' ins Leben gerufen, um ein besseres Verstaendnis fuer die Funktionsweise der Arbeitsmaerkte fuer Akademiker zu entwickeln und neue Ansatzpunkte abzuleiten, wie die Probleme der Akademikerarbeitslosigkeit und des Fachkraeftemangels angegangen werden koennen. Der Beitragsband enthaelt die Beitraege aus den Einzelprojekten, die im Rahmen einer groesseren Konferenz beim Institut fuer Arbeitsmarkt- und Berufsforschung der Bundesanstalt fuer Arbeit diskutiert und danach ueberarbeitet worden sind. Auch die Korreferate sind dokumentiert. Wie die Tagung ist auch der Band in vier Themenkomplexe gegliedert: 1. Die Reaktionen der Unternehmen auf den Fachkraeftemangel; 2. Die Anpassung von Studierenden auf sich annaehernde Arbeitsmarktperspektiven; 3. Auf die Mobilitaet junger Akademiker; 4. Trends und Abschaetzungen des zukuenftiger Bedarfs an Akademikern.' (Autorenreferat)SIGLEAvailable from IAB-95-1300-33 BM 796 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Genome scan for childhood and adolescent obesity in German families

Objective: Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. Methods: The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 ± 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. Results: The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. Conclusion: We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity

Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3

We describe a large family with disproportionate short stature and bone dysplasia from Nias in which we observed differences in severity when comparing the phenotypes of affected individuals from two remote branches. We conducted a linkage scan in the more severely affected family branch and determined a critical interval of 4.7 cM on chromosome 11. Sequencing of the primary candidate gene TBX10 did not reveal a disease-causing variant. When performing whole exome sequencing we noticed a homozygous missense variant in B3GAT3, c.419C > T [p.(Pro140Leu)]. B3GAT3 encodes beta-1,3-glucuronyltransferase-I (GlcAT-I). GlcAT-I catalyzes an initial step of proteoglycan synthesis and the mutation p. (Pro140Leu) lies within the donor substrate-binding subdomain of the catalytic domain. In contrast to the previously published mutation in B3GAT3, c.830G > A [p.(Arg277Gln)], no heart phenotype could be detected in our family. Functional studies revealed a markedly reduced GlcAT-I activity in lymphoblastoid cells from patients when compared to matched controls. Moreover, relative numbers of glycosaminoglycan (GAG) side chains were decreased in patient cells. We found that Pro140Leu-mutant GlcAT-I cannot efficiently transfer GlcA to the linker region trisaccharide. This failure results in a partial deficiency of both chondroitin sulfate and heparan sulfate chains. Since the phenotype of the Nias patients differs from the Larsen-like syndrome described for patients with mutation p.(Arg277Gln), we suggest mutation B3GAT3:p.(Pro140Leu) to cause a different type of GAG linkeropathy showing no involvement of the heart

Infrastructure, the economy and policy

The role of infrastructure in economic growth and development has been the subject of continued debate, yet no consensus has been achieved in the literature. This thesis examines the economic effect of infrastructure based on new evidence from China. We add to understanding of this complex phenomenon by focussing at micro levels, i.e., firm-level and household level with a focus on three critical infrastructure sectors: transport, renewable energy and information communication technologies. We employ a series of datasets on infrastructure, firm performance, and household economy from China in our examinations. Our first empirical study focuses on the economic effects of city’s ICT infrastructure on firm performance. We have found that the improvement of city’s ICT infrastructure positively improved firm’s profitability, marketing, and innovation. By taking advantage of an exogenous variation of city’s ICT using the telecommunication upgrade as a natural experiment, we establish the causal impact of city’s ICT infrastructure on firm profitability. We also identify the mechanisms in which ICTs impact firm performance, including the firm’s efficiency, firm’s labour, and firm cost. Our second empirical study focuses on the renewable energy sector and its influence on China’s rural household economy over the past two decades. We provide empirical evidence in this under-investigated area of research, and have found that renewable energy, including bioenergy, solar energy, and hydropower energy, indeed improved the rural household economy in China. In the third empirical study, we then focus on the impact of improved transport infrastructure connectivity on the litigation risks of listed firms in China. Based on a natural experiment on China’s highspeed rail system construction, we have found that the improvement of transport infrastructure connectivity reduced firm’s litigation risks. This study shows that the impact of improved transport connectivity on listed firms’ litigation risk stem from the reduction of information asymmetry, and also the increase of external regulations and monitoring. Overall, we have found evidence that transport infrastructure, renewable energy infrastructure and ICT infrastructure played a positive and critical role in the economic development from the perspectives of firm performance and household economy, and also provide in-depth analysis of the underlying mechanisms. The findings in this thesis offer evidence for policymakers that improvement of infrastructure contributes to the productivity, economic growth and social development, and reasonable deployment of infrastructure could pay off.</p

DEPDC5

Recent studies reported DEPDC5 loss-of-function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n=11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes