De novo Mutation Enables NOTCH3ECD Aggregation and Mitochondrial Dysfunction via Interactions with BAX and BCL-2

2022 ◽  
pp. 1-15
Author(s):  
Ruijie Liu ◽  
Chenhao Gao ◽  
Junkui Shang ◽  
Ruihua Sun ◽  
Wenjing Wang ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Autosomal Dominant ◽  
De Novo ◽  
Small Vessel Disease ◽  
Clinical Information ◽  
Cell Counting ◽  
De Novo Mutation ◽  
Vessel Disease ◽  
Notch3 Mutation

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear. Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL. Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro. The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis. Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G >  A, p. A564T) in two pedigrees. In vitro, the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis. Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations.

scholarly journals Novel Cysteine-Sparing Hypomorphic NOTCH3 A1604T Mutation Observed in a Family With Migraine and White Matter Lesions

2021 ◽  
Vol 7 (3) ◽  
pp. e584
Author(s):  
Snjolaug Arnardottir ◽  
Francesca Del Gaudio ◽  
Stefanos Klironomos ◽  
Eike-Benjamin Braune ◽  
Ariane Araujo Lombraña ◽  
...  
Keyword(s):  
White Matter ◽  
Target Genes ◽  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
White Matter Lesions ◽  
Proteolytic Processing ◽  
Neurologic Symptoms ◽  
Downstream Target ◽  
Vessel Disease ◽  
Notch3 Mutation

ObjectiveTo conduct a clinical study of a family with neurologic symptoms and findings carrying a novel NOTCH3 mutation and to analyze the molecular consequences of the mutation.MethodsWe analyzed a family with complex neurologic symptoms by MRI and neurologic examinations. Exome sequencing of the NOTCH3 locus was conducted, and whole-genome sequencing was performed to identify COL4A1, COL4A2, and HTRA1 mutations. Cell lines expressing the normal or NOTCH3A1604T receptors were analyzed to assess proteolytic processing, cell morphology, receptor routing, and receptor signaling.ResultsCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease (SVD) and caused by mutations in the NOTCH3 gene. Most CADASIL mutations alter the number of cysteine residues in the extracellular domain of the NOTCH3 receptor, but in this article, we describe a family in which some members carry a novel cysteine-sparing NOTCH3 mutation (c.4810 G>A, p.Ala1604Thr). Two of 3 siblings heterozygous for the NOTCH3A1604T mutation presented with migraine and white matter lesions (WMLs), the latter of a type related to but distinct from what is normally observed in CADASIL. Two other members instead carried a novel COL4A1 missense mutation (c.4795 G>A; p.(Ala1599Thr)). The NOTCH3A1604T receptor was aberrantly processed, showed reduced presence at the cell surface, and less efficiently activated Notch downstream target genes.ConclusionsWe identify a family with migraine and WML in which some members carry a cysteine-sparing hypomorphic NOTCH3 mutation. Although a causal relationship is not established, we believe that the observations contribute to the discussion on dysregulated Notch signaling in cerebral SVDs.

scholarly journals Drug-Coated Balloon-Only Angioplasty Outcomes in Diabetic and Nondiabetic Patients with De Novo Small Coronary Vessels Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Botey Katamu Benjamin ◽  
Wenjie Lu ◽  
Zhanying Han ◽  
Liang Pan ◽  
Xi Wang ◽  
...  
Keyword(s):  
De Novo ◽  
Small Vessel Disease ◽  
Independent Predictor ◽  
Coronary Vessels ◽  
Target Lesion ◽  
Target Lesion Revascularization ◽  
Vessel Disease ◽  
One Year ◽  
Target Lesion Failure ◽  
Drug Coated Balloon

Background. The revascularization of small vessels using drug-eluting stents remains challenging. The use of the drug-coated balloon is an attractive therapeutic strategy in de novo lesions in small coronary vessels, particularly in the diabetic group. This study aimed to assess the outcomes of DCB-only angioplasty in small vessel disease. Methods. A total of 1198 patients with small vessel disease treated with DCB-only strategy were followed. Patients were divided into the diabetic and nondiabetic groups. Clinical and angiographical follow-up were organized at 12 months. The primary endpoints were target lesion failure and secondary major adverse cardiac events. Results. There was a significantly higher rate of target lesion failure among diabetic patients compared to nondiabetic [17 (3.9%) vs. 11 (1.4%), P = 0.006 ], taken separately, the rate of target lesion revascularization significantly differed between groups with a higher rate observed in the diabetic group [9 (2%) vs. 4 (0.5%), P = 0.014 ]. Diabetes mellitus remained an independent predictor for TLF (HR: 2.712, CI: 1.254–5.864, P = 0.011 ) and target lesion revascularization (HR: 3.698, CI: 1.112–12.298, P = 0.033 ) after adjustment. However, no significant differences were observed between groups regarding the target vessel myocardial infarction (0.6% vs. 0.1%, P = 0.110 ) and MACE [19 (4.4%) vs. 21 (2.7%), P = 0.120 ]. Conclusion. Drug-coated balloon-only treatment achieved lower incidence rates of TLF and MACE. Diabetes is an independent predictor for target lesion failure and target lesion revascularization at one year following DCB treatment in small coronary vessels. We observed no significant differences between groups regarding MACE in one year.

scholarly journals MRI Relaxometry for Quantitative Analysis of USPIO Uptake in Cerebral Small Vessel Disease

2019 ◽  
Vol 20 (3) ◽  
pp. 776 ◽  
Author(s):  
Michael Thrippleton ◽  
Gordon Blair ◽  
Maria Valdes-Hernandez ◽  
Andreas Glatz ◽  
Scott Semple ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Blood Volume ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Minor Stroke ◽  
Vessel Disease ◽  
Wide Range

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.

Generation, characterization, and molecular cloning of the Noerg-1 mutation of rhodopsin in the mouse

2005 ◽  
Vol 22 (5) ◽  
pp. 619-629 ◽  
Author(s):  
LAWRENCE H. PINTO ◽  
MARTHA H. VITATERNA ◽  
KAZUHIRO SHIMOMURA ◽  
SANDRA M. SIEPKA ◽  
ERIN L. MCDEARMON ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Genomic Sequence ◽  
Outer Nuclear Layer ◽  
Dna Polymorphisms ◽  
Fundus Photography ◽  
Induced Mutations ◽  
Coding Region ◽  
Optomotor Response

We performed genome-wide mutagenesis of C57BL/6J mice using the mutagen N-ethyl-N-nitrosourea (ENU) and screened the third generation (G3) offspring for visual system alterations using electroretinography and fundus photography. Several mice in one pedigree showed characteristics of retinal degeneration when tested at 12–14 weeks of age: no recordable electroretinogram (ERG), attenuation of retinal vessels, and speckled pigmentation of the fundus. Histological studies showed that the retinas undergo a photoreceptor degeneration with apoptotic loss of outer nuclear layer nuclei but visual acuity measured using the optomotor response under photopic conditions persists in spite of considerable photoreceptor loss. The Noerg-1 mutation showed an autosomal dominant pattern of inheritance in progeny. Studies in early postnatal mice showed degeneration to occur after formation of partially functional rods. The Noerg-1 mutation was mapped genetically to chromosome 6 by crossing C57BL/6J mutants with DBA/2J or BALB/cJ mice to produce an N2 generation and then determining the ERG phenotypes and the genotypes of the N2 offspring at multiple loci using SSLP and SNP markers. Fine mapping was accomplished with a set of closely spaced markers. A nonrecombinant region from 112.8 Mb to 115.1 Mb was identified, encompassing the rhodopsin (Rho) coding region. A single nucleotide transition from G to A was found in the Rho gene that is predicted to result in a substitution of Tyr for Cys at position 110, in an intradiscal loop. This mutation has been found in patients with autosomal dominant retinitis pigmentosa (RP) and results in misfolding of rhodopsin expressed in vitro. Thus, ENU mutagenesis is capable of replicating mutations that occur in human patients and is useful for generating de novo models of human inherited eye disease. Furthermore, the availability of the mouse genomic sequence and extensive DNA polymorphisms made the rapid identification of this gene possible, demonstrating that the use of ENU-induced mutations for functional gene identification is now practical for individual laboratories.

Activating NOTCH3 mutation in a patient with small-vessel-disease of the Brain

2008 ◽  
Vol 29 (3) ◽  
pp. 452-452 ◽  
Author(s):  
Charles Fouillade ◽  
Hugues Chabriat ◽  
Florence Riant ◽  
Manuèle Mine ◽  
Minh Arnoud ◽  
...  
Keyword(s):  
Small Vessel Disease ◽  
Small Vessel ◽  
Vessel Disease ◽  
Notch3 Mutation ◽  
The Brain

scholarly journals Cysteine-Altering NOTCH3 Variants Are a Risk Factor for Stroke in the Elderly Population

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3562-3569 ◽  
Author(s):  
Remco J. Hack ◽  
Julie W. Rutten ◽  
Thomas N. Person ◽  
Jiang Li ◽  
Ayesha Khan ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Elderly Population ◽  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
Brain Magnetic Resonance Imaging ◽  
The Elderly ◽  
Small Vessel ◽  
Resonance Imaging ◽  
Vessel Disease

Background and Purpose: Cysteine altering NOTCH3 variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, have a population frequency of 1:300 worldwide. Using a large population database, and taking genotype as a starting point, we aimed to determine whether individuals harboring a NOTCH3 cysteine altering variant have a higher load of small vessel disease markers on brain magnetic resonance imaging than controls, as well as a higher risk of stroke and cognitive impairment. Methods: A cross-sectional study using integrated clinical, neuroimaging, and whole-exome sequencing data of 92 456 participants from the Geisinger DiscovEHR initiative cohort. The case group consisted of individuals harboring a NOTCH3 cysteine altering variant (n=118). The control group consisted of randomly selected age- and sex-matched individuals who did not have any nonsynonymous variants in NOTCH3 (n=184). Medical records including brain magnetic resonance imagings were evaluated for clinical and neuroimaging findings associated with small vessel disease. Group comparisons were done using Fisher exact test and ordinal logistic regression models. Risk of stroke was assessed using Cox regression. Results: Of the 118 cases, 39.0% were men, mean age 58.1±16.9 years; 12.6% had a history of stroke, compared with 4.9% of controls. The risk of stroke was significantly increased after age 65 years (hazard ratio, 6.0 [95% CI, 1.4–26.3]). Dementia, mild cognitive impairment, migraine with aura and depression were equally prevalent in cases and controls. Twenty-nine cases (25%) and 45 controls (24%) had an available brain magnetic resonance imaging. After age 65 years, cases had a higher white matter lesion burden and more lacunes. A severe small vessel disease phenotype compatible with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy was rarely seen. Conclusions: Cysteine altering NOTCH3 variants are an important contributor to the risk of stroke, lacunes, and white matter hyperintensities in the elderly population.

scholarly journals Lowe syndrome identified in the offspring of an oocyte donor who was an unknown carrier of a de novo mutation: a case report and review of the literature

2019 ◽  
Vol 13 (1) ◽  
Author(s):  
P. Tatsi ◽  
G. E. Papanikolaou ◽  
T. Chartomatsidou ◽  
I. Papoulidis ◽  
A. Athanasiadis ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Ethical Issues ◽  
De Novo ◽  
Dent Disease ◽  
De Novo Mutation ◽  
Lowe Syndrome ◽  
Genetic Constitution ◽  
Preimplantation Genetic Testing ◽  
Oculocerebrorenal Syndrome

Abstract Background Oculocerebrorenal syndrome of Lowe is an X-linked disorder with very low prevalence in the general population. The OCRL gene encodes the protein phosphatidylinositol 4,5-bisphosphate-5-phosphatase, a lipid phosphatase, located in the trans-Golgi network. Point mutations in the OCRL gene cause Lowe syndrome and Dent disease, which are characterized as a multisystemic disorder. The symptoms of Lowe syndrome are expressed primarily as dysfunction of the eyes, kidneys, and the central nervous system. Case presentation This report describes a case of a 31-year-old Georgian woman with a de novo pathogenic mutation causing oculocerebrorenal syndrome of Lowe, who was a volunteer in an oocyte donation program for in vitro fertilization purposes, and the outcome of the treatments of this particular donor’s oocyte receivers, describing the implications of the mutation for the children born as a result of the treatments. It raises important medical and ethical issues about the necessity of genetic testing of oocyte donors and the possibility of rare genetic disorders being inherited by the offspring of donors. Conclusion This particular case indicates the legal, medical, and emotional risks of utilizing donor oocytes from phenotypically healthy women, whose genetic constitution is unknown in terms of being silent carriers of rare diseases. In addition, all the necessary actions were followed; the further examinations that are required are mentioned. The donor and the offspring should be further tested. The remaining cryopreserved embryos should be destroyed or preimplantation genetic testing should be performed before they are utilized. Finally, all the people involved, the treated couples and the donor, alongside her family, should follow genetic and psychological counselling.

Association of autosomal dominant polycystic kidney disease with cerebral small vessel disease

2021 ◽  
pp. 0271678X2110378
Author(s):  
Woo-Jin Lee ◽  
Keun-Hwa Jung ◽  
Hyunjin Ryu ◽  
Kook-Hwan Oh ◽  
Jeong-Min Kim ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Polycystic Kidney ◽  
Glymphatic System ◽  
Vessel Disease ◽  
Autosomal Dominant Polycystic Kidney

Cilia dysfunction in autosomal-dominant polycystic kidney disease (ADPKD) may impair the integrity of glymphatic system and be implicated in the progression of cerebral small vessel disease (SVD), although the link between the two diseases has not been investigated. We evaluated the association of ADPKD pathology with SVD pattern and severity. Overall, 304 individuals in an ADPKD (chronic kidney disease stage ≤4 and age ≥50 years) cohort and their age, sex, and estimated glomerular filtration rate (eGFR)-matched controls were retrospectively included. ADPKD severity was classified into 1 A-B, 1 C, and 1 D-E, according to age and height-adjusted total kidney volume. SVD parameters included white-matter hyperintensity (WMH) severity scale, enlarged perivascular space (ePVS) score, and degree of lacunes or cerebral microbleeds (CMBs). After adjustments for age, sex, eGFR, and cerebrovascular risk factor parameters, ADPKD was associated with higher ePVS scores ( P < 0.001), but not with the WMH severity or degree of lacunes or CMBs. In the ADPKD subgroup, higher ADPKD severity class was associated with higher ePVS scores ( P < 0.001), WMH severity ( P = 0.003), and degree of lacunes ( P = 0.002). ADPKD associated cilia dysfunction may induce chronic cerebral glymphatic system dysfunction, which may contribute to the specific progression of ePVS compared with other SVD markers.

scholarly journals Drug Coated Balloon-Only Strategy in De Novo Lesions of Large Coronary Vessels

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Mark Rosenberg ◽  
Matthias Waliszewski ◽  
Florian Krackhardt ◽  
Kenneth Chin ◽  
Wan Azman Wan Ahmad ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
De Novo ◽  
Small Vessel Disease ◽  
Coronary Vessels ◽  
Large Vessel ◽  
Attractive Alternative ◽  
Interventional Treatment ◽  
Vessel Disease ◽  
Large Coronary Arteries ◽  
Large Vessels

Objectives. We analyzed the efficacy of drug coated balloons (DCB) as a stand-alone-therapy in de novo lesions of large coronary arteries. DCBs seem to be an attractive alternative for the stent-free interventional treatment of de novo coronary artery disease (CAD). However, data regarding a DCB-only approach in de novo CAD are currently limited to vessels of small caliber. Methods. By means of propensity score (PS) matching 234 individuals with de novo CAD were identified with similar demographic characteristics. This patient population was stratified in a 1:1 fashion according to a reference vessel diameter cut-off of 2.75 mm in small and large vessel disease. The primary endpoint was the rate of clinically driven target lesion revascularization (TLR) at 9 months. Results. Patients with small vessel disease had an average reference diameter of 2.45 ± 0.23 mm, while the large vessel group averaged 3.16 ± 0.27 mm. Regarding 9-month major adverse cardiac event (MACE), 5.7% of the patients with small and 6.1% of the patients with large vessels had MACE (p=0.903). Analysis of the individual MACE components revealed a TLR rate of 3.8% in small and 1.0% in large vessels (p=0.200). Of note, no thrombotic events in the DCB treated coronary segments occurred in either group during the 9-month follow-up. Conclusions. Our data demonstrate for the first time that DCB-only PCI of de novo lesions in large coronary arteries (>2.75 mm) is safe and as effective. Interventional treatment for CAD without permanent or temporary scaffolding, demonstrated a similar efficacy for large and small vessels.

Sign in / Sign up

Export Citation Format

Share Document