NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, ...neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare, and only 1 patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report 3 additional patients with a de novo deletion encompassing NR4A2: 2 patients have deletions encompassing only NR4A2 gene and 1 patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance.
Diminazene aceturate (DA) is the active component of some trypanocidal drugs used for the treatment of animals infected with trypanosomosis and babesiosis. Residues of DA may cause hepatotoxic and ...nephrotoxic effects. Therefore, the purpose of this study was to investigate the occurrence of oxidative stress, i.e., changes in the antioxidant defense system of rats treated with a single dose of 3.5 mg kg
−1
of DA. All treatments were intramuscularly administered, and evaluations were performed on days 7 and 21 post-treatment (PT). Liver and kidney samples were collected and evaluated by histopathology and oxidative stress parameters (thiobarbituric acid-reactive species, catalase, superoxide dismutase, carbonyl, non-protein thiols, and reduced glutathione). Finally, blood was collected to determine seric DA concentration. Superoxide dismutase (SOD) and catalase (CAT) activities in liver and kidney of rats were dramatically inhibited (
p
< 0.05) compared to the control group on day 21 PT. This difference is related to the concomitant increase (
p
< 0.05) in malondialdehyde (MDA) content, which was identified by an increase in thiobarbituric acid-reactive species (TBARS) levels. The carbonyl levels did not differ between groups (
p
> 0.05). Both non-protein thiols (NPSH) and glutathione (GSH) levels in liver and kidney decreased (
p
< 0.05) on day 21 PT. Chromatographic analyses showed lower levels of DA on day 21 PT compared to day 7 PT. A negative correlation was observed between DA concentration in serum and lipid peroxidation in liver and kidney tissues on 21 days PT. Histopathology revealed vacuolar degeneration in liver and kidney samples on day 21 PT. Our findings indicate that DA could cause oxidative damage to liver and kidney of rats.
Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well‐known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), ...encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27—41%) or presenting with an overlapping syndrome (5/27—19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.
Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental ...delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.
We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.
We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators’ recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.
Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.
To determine whether vascular function assessed by low-flow-mediated constriction (L-FMC), a novel non-invasive method, complements the information obtained with "traditional" flow-mediated ...dilatation (FMD).
In protocol 1, 12 healthy young volunteers underwent FMD and L-FMC measurements at rest and immediately after isometric exercise of the same hand. In protocol 2, 24 patients with coronary artery disease, 24 with congestive heart failure, 24 hypertensive patients and 64 healthy volunteers were enrolled to undergo L-FMC and FMD measurements.
In protocol 1, exercise was associated with mean (SD) increases in radial artery blood flow, diameter and L-FMC (from -5.1 (1.5)% to -7.8 (3.4)%, p<0.05), while FMD was significantly blunted (from 6.0 (2.4)% to 3.0 (3.2)%, p<0.05). In protocol 2, both FMD and L-FMC were blunted in the patient groups. Receiver operating curve analysis showed that, as compared with FMD alone, the combination of L-FMC and FMD significantly improved the sensitivity and specificity in detecting patients diagnosed with cardiovascular disease (p<0.05).
In the first protocol, FMD and L-FMC were shown to be reciprocally regulated. A blunted FMD may, in certain cases, be an expression of increased resting vascular activation and not only of impaired endothelial function. In the second protocol, a statistical approach showed that implementation of L-FMC provides a better characterisation than FMD of vascular function in cardiovascular disease. Vascular (endothelial) function is a complex phenomenon which requires a multifaceted approach; it is suggested that a combination of L-FMC and FMD will provide additive and complementary information to "traditional" FMD measurements.
Background: The relevance of registries as a key component for developing clinical research for rare diseases (RD) and improving patient care has been acknowledged by most stakeholders. As recent ...studies pointed to several limitations of RD registries our challenge was (1) to improve standardization and data comparability; (2) to facilitate interoperability between existing RD registries; (3) to limit the amount of incomplete data; (4) to improve data quality. This report describes the innovative concept of the DM-Scope Registry that was developed to achieve these objectives for Myotonic Dystrophy (DM), a prototypical example of highly heterogeneous RD. By the setting up of an integrated platform attractive for practitioners use, we aimed to promote DM epidemiology, clinical research and patients care management simultaneously.Results: The DM-Scope Registry is a result of the collaboration within the French excellence network established by the National plan for RDs. Inclusion criteria is all genetically confirmed DM individuals, independently of disease age of onset. The dataset includes social-demographic data, clinical features, genotype, and biomaterial data, and is adjustable for clinical trial data collection. To date, the registry has a nationwide coverage, composed of 55 neuromuscular centres, encompassing the whole disease clinical and genetic spectrum. This widely used platform gathers almost 3000 DM patients (DM1 n = 2828, DM2 n = 142), both children (n = 322) and adults (n = 2648), which accounts for > 20% of overall registered DM patients internationally. The registry supported 10 research studies of various type i.e. observational, basic science studies and patient recruitment for clinical trials.Conclusion: The DM-Scope registry represents the largest collection of standardized data for the DM population. Our concept improved collaboration among health care professionals by providing annual follow-up of quality longitudinal data collection. The combination of clinical features and biomolecular materials provides a comprehensive view of the disease in a given population. DM-Scope registry proves to be a powerful device for promoting both research and medical care that is suitable to other countries. In the context of emerging therapies, such integrated platform contributes to the standardisation of international DM research and for the design of multicentre clinical trials. Finally, this valuable model is applicable to other RDs.
Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death in young adults, with a prevalence of 1/500 in the general population. HCM is a genetic disease usually related ...to a sarcomeric gene mutation. Despite advances in knowledge, elucidation of the genetic cause is reached in only 30–60% of cases with conventional Sanger sequencing and analysis of a limited number of genes (usually the five major sarcomeric genes). We hypothesized that high-throughput sequencing of a large panel of genes will allow a more comprehensive evaluation of the etiologic spectrum of HCM.
We used high-throughput sequencing technology, with a panel of 107 genes (all the various cardiomyopathies and arrhythmia genes) that we recently developed (Nimblegen capture then Illumina MiSeq sequencing), in a cohort of 97 unrelated patients with HCM. We detected 2740 variants including 99 variants that we classified as pathogenic using restrictive criteria. A pathogenic mutation was identified (i) in 31 patients (32% of cohort of patients) in the group of 5 conventional sarcomeric genes (MYBPC3, MYH7, TNNT2, MYL2, TNNI3) including patients with multiple mutations, (ii) in 8 patients (8%) with a mutation in the group of additional sarcomeric genes (such as MYH6), (iii) in 4 patients (4%) with a mutation in the group of non-sarcomeric genes previously associated to HCM (such as GLA responsible for Fabry disease) and (iv) in additional patients with a mutation in new genes not yet reported in HCM (such as AKAP9).
High-throughput sequencing of a large panel of genes associated with hereditary heart diseases allowed us to determine the large genetic spectrum of HCM. We confirmed the prominent role of sarcomeric genes, highlighted the role of non-sarcomeric causes (some with specific therapeutics) and identified mutations in potential new genes responsible for the disease.
PDF
