Search

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN ( n = 237), painless-DPN ( n = 309), painful-SFN ( n = 547) and painless-SFN ( n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% ( n = 142/784) of painful neuropathy patients vs. 15.2% ( n = 52/341) of painless neuropathy patients (17.3% ( n = 41/237) for painful-DPN patients, 14.9% ( n = 46/309) for painless-DPN patients, 18.5% ( n = 101/547) for painful-SFN patients, and 18.8% ( n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A . The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Dilated cardiomyopathy is a heterogeneous disease characterized by multiple genetic and environmental etiologies. The majority of patients are treated the same despite these differences. The cardiac transcriptome provides information on the patient's pathophysiology, which allows targeted therapy. Using clustering techniques on data from the genotype, phenotype, and cardiac transcriptome of patients with early- and end-stage dilated cardiomyopathy, more homogeneous patient subgroups are identified based on shared underlying pathophysiology. Distinct patient subgroups are identified based on differences in protein quality control, cardiac metabolism, cardiomyocyte function, and inflammatory pathways. The identified pathways have the potential to guide future treatment and individualize patient care., Competing Interests: The research leading to these results has received funding from the DCVA DOUBLE DOSE grant. We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation and CVON Arena-PRIME, 2017-18. Drs Verdonschot and Nabben are supported by a Dutch Heart Foundation grant. Heymans receives personal fees for scientific advice to Astra-Zeneca, Pfizer, Novo Nordisk and CSL Behringer. All other authors have reported that they have no relationships relevant to the contents of this paper., (© 2023 The Authors.)

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging., (© 2023. The Author(s).)

Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1., (© 2021. The Author(s).)

Aims: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups., Methods and Results: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping., Conclusion: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cardiac resynchronization therapy (CRT) is an established therapy in patients with dilated cardiomyopathy (DCM) and conduction disorders. Still, one-third of the patients with DCM do not respond to CRT. This study aims to depict the underlying cardiac pathophysiological processes of nonresponse to CRT in patients with DCM using endomyocardial biopsies., Methods: Within the Maastricht and Innsbruck registries of patients with DCM, 99 patients underwent endomyocardial biopsies before CRT implantation, with histological quantification of fibrosis and inflammation, where inflammation was defined as >14 infiltrating cells/mm 2 . Echocardiographic left ventricular end-systolic volume reduction ≥15% after 6 months was defined as response to CRT. RNA was isolated from cardiac biopsies of a representative subset of responders and nonresponders., Results: Sixty-seven patients responded (68%), whereas 32 (32%) did not respond to CRT. Cardiac inflammation before implantation was negatively associated with response to CRT (25% of responders, 47% of nonresponders; odds ratio 0.3 [0.12-0.76]; P =0.01). Endomyocardial biopsies fibrosis did not relate to CRT response. Cardiac inflammation improved the robustness of prediction beyond well-known clinical predictors of CRT response (likelihood ratio test P <0.001). Cardiac transcriptomic profiling of endomyocardial biopsies reveals a strong proinflammatory and profibrotic signature in the hearts of nonresponders compared with responders. In particular, COL1A1, COL1A2, COL3A1, COL5A1, POSTN, CTGF, LOX, TGFβ1, PDGFRA, TNC, BGN , and TSP2 were significantly higher expressed in the hearts of nonresponders., Conclusions: Cardiac inflammation along with a transcriptomic profile of high expression of combined proinflammatory and profibrotic genes are associated with a poor response to CRT in patients with DCM.

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd TTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored., (Copyright © 2017 Elsevier Inc. All rights reserved.)