De novo mutations (DNMs) are important players in heritable diseases and evolution. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultradeep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined ∼4.5 kb of the FGFR3 coding region in sperm DNA from older and younger donors. We identified sites with variant allele frequencies (VAFs) of 10−4 to 10−5, with an overall mutation frequency of the region of ∼6 × 10−7. Some of the substitutions are recurrent and are found at a higher VAF in older donors than in younger ones or are found exclusively in older donors. Also, older donors harbor more mutations associated with congenital disorders. Other mutations are present in both age groups, suggesting that these might result from a different mechanism (e.g., postzygotic mosaicism). We also observe that independent of age, the frequency and deleteriousness of the mutational spectra are more similar to COSMIC than to gnomAD variants. Our approach is an important strategy to identify mutations that could be associated with a gain of function of the receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.
It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults. As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are “Janus”-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues.
Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region of NHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest gene NHLRC1 in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion upon NHLRC1 knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data. NHLRC1 holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.
Cystic fibrosis (CF) is a monogenic disease, characterized by massive chronic lung inflammation. The observed variability in clinical phenotypes in monozygotic CF twins is likely associated with the extent of inflammation. This study sought to investigate inflammation-related aberrant DNA methylation in CF twins and to determine to what extent acquired methylation changes may be associated with lung cancer. Blood-based genome-wide DNA methylation analysis was performed to compare the DNA methylomes of monozygotic twins, from the European CF Twin and Sibling Study with various degrees of disease severity. Putatively inflammation-related and differentially methylated positions were selected from a large lung cancer case-control study and investigated in blood by targeted bisulphite next-generation-sequencing. An inflammation-related locus located in the Plakophilin-3 ( PKP3 ) gene was functionally analysed regarding promoter and enhancer activity in presence and absence of methylation using luciferase reporter assays. We confirmed in a unique cohort that monozygotic twins, even if clinically discordant, have only minor differences in global DNA methylation patterns and blood cell composition. Further, we determined the most differentially methylated positions, a high proportion of which are blood cell-type-specific, whereas others may be acquired and thus have potential relevance in the context of inflammation as lung cancer risk factors. We identified a sequence in the gene body of PKP3 which is hypermethylated in blood from CF twins with severe phenotype and highly variably methylated in lung cancer patients and controls, independent of known clinical parameters, and showed that this region exhibits methylation-dependent promoter activity in lung epithelial cells.
ZusammenfassungBei der Beurteilung der gesundheitlichen Eignung zum Lenken eines Kraftfahrzeuges ist die öffentliche Sicherheit (Unfallprävention) das vorrangige Ziel. Der generelle Zugang zu Mobilität sollte jedoch nicht eingeschränkt werden, wenn kein besonderes Risiko für die öffentliche Sicherheit besteht. Für Menschen mit Diabetes mellitus sind im Führerscheingesetz (FSG) und in der Führerscheingesetz-Gesundheitsversorgung (FSG-GV) wichtige Aspekte zur Fahrsicherheit in Zusammenhang mit akuten und chronischen Komplikationen der Erkrankung geregelt. Zu den kritischen Komplikationen, die für die Verkehrssicherheit relevant sind, gehören schwere Hypoglykämie, ausgeprägte Hyperglykämie und Hypoglykämiewahrnehmungsstörung, sowie schwere Retinopathie und Neuropathie, weiters fortgeschrittene Nierenerkrankung und bestimmte kardiovaskuläre Manifestationen. Bei Verdacht auf Präsenz einer dieser Akutkomplikationen oder Folgeschäden ist eine genaue Evaluierung erforderlich.Darüber hinaus ist die individuelle antihyperglykämische Medikation auf vorhandenes Potenzial für Hypoglykämien zu überprüfen. Sulfonylharnstoffe, Glinide und Insulin gehören in diese Gruppe und sind daher automatisch mit der Auflage einer 5‑jährigen Befristung des Führerscheines assoziiert. Metformin, DPP-4-Hemmer (Dipeptidyl-Peptidase-4-Hemmer, Gliptine), SGLT2-Hemmer (Sodium-dependent-glucose-transporter‑2 inhibitors, Gliflozine), Glitazone und die zu injizierenden GLP-1 Analoga (GLP‑1 Rezeptor Agonisten) weisen kein Hypoglykämiepotential auf und sind daher nicht mit einer Befristung verbunden.Die FSG-GV gibt Spielraum für Interpretation, sodass im Folgenden spezifische Themen zur Fahrsicherheit für Menschen mit Diabetes mellitus aus fachärztlicher und verkehrsrelevanter Sicht aufgearbeitet wurden. Dieses Positionspapier dient zur Unterstützung von Personen, die mit dieser herausfordernden Materie befasst sind.
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