The Saccharomyces cerevisiae gene VPS35 encodes a component of the retromer complex which is involved in vesicle transport from endosomes to the trans-Golgi network. Yeast and human VPS35 orthologs ...are highly conserved and mutations in human VPS35 cause an autosomal dominant form of late-onset Parkinson disease (PD). We now show that deletion of VPS35 in yeast (vps35Δ) leads to a dose-dependent growth defect towards copper. This increased sensitivity could be rescued by transformation with yeast wild-type VPS35 but not by the expression of a construct harboring the yeast equivalent (i.e. D686N) of the most commonly identified VPS35-associated PD mutation, p.D620N. In addition, we show that expression of one copy of α-synuclein, which is known to directly interact with copper, leads to a pronounced aggravation of copper toxicity in vps35Δ cells, thereby linking the regulation of copper homeostasis by Vps35p in yeast to one of the key molecules in PD pathophysiology.
•Deletion of the Parkinson-associated VPS35 in yeast leads to increased copper toxicity.•PD-associated VPS35 mutations seem to act via a loss-of-function mechanism.•Expression of α-synuclein leads to an aggravation of copper sensitivity in yeast.
Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate ...markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics).
In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed.
Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration.
Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.
Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for ...homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson's disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration ...remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca
channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson's disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca
signals and Ca
-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson's mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca
-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson's. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca
-dependent neurodegeneration in Parkinson's disease.
Centers for rare diseases serve as contact points for patients with complex, often undiagnosed complaints and persistent somatic symptoms of heterogeneous origin. Little is known about psychological ...distress of patients consulting these centers.
To better understand psychological distress of adult patients presenting at a center for rare diseases by determining the proportion of patients screening positive for depressive, anxiety, and somatic symptom disorders (SSD) and to identify factors associated with increased psychopathology.
Cross-sectional data from the routine care registry of the Martin Zeitz Center for Rare Diseases (MZCSE) at the University Medical Center Hamburg-Eppendorf in Germany was retrieved and analyzed. We included all adult patients presenting between October 01,2020 and September 30,2021, who gave written informed consent.
Sociodemographic variables, medical history and healthcare utilization, as well as validated measures to screen for a depressive disorder (PHQ-8), an anxiety disorder (GAD-7), and SSD (PHQ-15, SSD-12).
N = 167 patients were included (age 44.5 ± 14.3 years, 64.7% female). A total of 40.7% of the patients screened positive for a depressive disorder (PHQ-8 ≥ 10), 27.5% for an anxiety disorder (GAD-7 ≥ 10) and 45.0% screened positive for SSD (PHQ-15 ≥ 9 & SSD-12 ≥ 23). Factors associated with increased psychopathology included the number of symptoms, the number of different specialties consulted before and past psychotherapy.
Patients presenting at centers for rare diseases are likely to experience high rates of psychological distress. Systematically screening patients with rare and undiagnosed diseases for mental disorders can help to detect those at risk at an early stage and initiate adequate psychological care.
The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its ...well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient's primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation's aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria.
Abstract In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 ( C9orf72 ) and superoxide dismutase 1 ( SOD1 ) account for most ...familial and late-onset sporadic cases, whereas mutations in fused in sarcoma ( FUS ) can be identified in just around 5% of familial and 1% of overall sporadic cases. There are only few reports on de novo FUS mutations in juvenile ALS patients. To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted. Here, we screened a cohort of 14 early-onset sporadic ALS patients (onset age <35 years) to determine the frequency of mutations in C9orf72 , SOD1 , and FUS in this defined patient cohort. All patients were recruited prospectively by a single center in a period of 38 months. No mutations were detected in SOD1 or C9orf72 ; however, we identified 6 individuals (43%) carrying a heterozygous FUS mutation including 1 mutation that has not been described earlier (c.1504delG p.Asp502Thrfs*27). Genetic testing of parents was possible in 5 families and revealed that the mutations in these patients arose de novo. Three of the 6 identified patients presented with initial bulbar symptoms. Our study identifies FUS mutations as the most frequent genetic cause in early-onset ALS. Genetic testing of FUS thus seems indicated in sporadic early-onset ALS patients especially if showing predominant bulbar symptoms and an aggressive disease course.
Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include ...craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.
MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a ...MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn) and a missense variant of unknown significance in the fourth patient c.4013G > A p.(Ser1338Asn) in propeptide coding regions of COL2A1. Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype-phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1-negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).
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