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Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects’ fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects’ fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
Im vorliegenden Beitrag plädiere ich für ein Vorgehen, bei dem Kopulasätze generell als Beschreibungen von Situationen behandelt werden. Genauer nehme ich an, daß Sätze mit der Kopula 'sein' semantische Repräsentationen haben, die über eine darin vorkommende existenzquantifizierte Variable auf eine noch näher zu spezifizierende Situation referieren. Drei grundlegende Klassen von Fällen werden unterschieden: Erstens kann es sich bei der fraglichen Situation um einen durch das Prädikativ charakterisierten Zustand handeln, in dem sich das mit dem Subjektausdruck erfaßte Objekt befindet. Zweitens kann die Situation ein mit dem Subjektausdruck erfaßter Zustand sein, der über das Prädikativ eine zusätzliche Charakterisierung erhält. Und drittens kann die Situation auch ein Ereignis (im weiteren Sinne) sein, das nun entsprechend mit dem betreffenden Subjektausdruck erfaßt und durch das Prädikativ näher charakterisiert wird.
This paper is concerned with the fact that a number of adverbal modifications involve a systematic reinterpretation of at least one of the expressions connected by the operation in question. It offers an approach in which such transfers of meaning turn out to be a result of contextually controlled enrichments of an underspecified as well as a strictly compositionally structured semantic representation. The approach proposed is general for three reasons: First, it takes into account not only reinterpretations in temporal but also such in non-temporal modification. Second, it allows considering so-called secondary predications as a particular kind of adverbal modification. Third, it explains the respective reinterpretations within a uniform formal framework of meaning variation.