Cortical degeneration in frontotemporal lobar degeneration with TDP-43 proteinopathy caused by progranulin gene mutation

Familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is most commonly caused by progranulin (GRN) gene mutation. To characterize cortical degeneration in these cases, changes in density of the pathology across the cortical laminae of the frontal and temporal lobe were studied in seven cases of FTLD-TDP with GRN mutation using quantitative analysis and polynomial curve fitting. In 50% of gyri studied, neuronal cytoplasmic inclusions (NCI) exhibited a peak of density in the upper cortical laminae. Most frequently, neuronal intranuclear inclusions (NII) and dystrophic neurites (DN) exhibited a density peak in lower and upper laminae, respectively, glial inclusions (GI) being distributed in low densities across all laminae. Abnormally enlarged neurons (EN) were distributed either in the lower laminae or were more uniformly distributed across the cortex. The distribution of all neurons present varied between cases and regions, but most commonly exhibited a bimodal distribution, density peaks occurring in upper and lower laminae. Vacuolation primarily affected the superficial laminae and density of glial cell nuclei increased with distance across the cortex from pia mater to white matter. The densities of the NCI, GI, NII, and DN were not spatially correlated. The laminar distribution of the pathology in GRN mutation cases was similar to previously reported sporadic cases of FTLD-TDP. Hence, pathological changes initiated by GRN mutation, and by other causes in sporadic cases, appear to follow a parallel course resulting in very similar patterns of cortical degeneration in FTLD-TDP.

Mutation at the Human D1S80 Minisatellite Locus

Little is known about the general biology of minisatellites. The purpose of this study is to examine repeat mutations from the D1S80 minisatellite locus by sequence analysis to elucidate the mutational process at this locus. This is a highly polymorphic minisatellite locus, located in the subtelomeric region of chromosome 1. We have analyzed 90,000 human germline transmission events and found seven (7) mutations at this locus. The D1S80 alleles of the parentage trio, the child, mother, and the alleged father were sequenced and the origin of the mutation was determined. Using American Association of Blood Banks (AABB) guidelines, we found a male mutation rate of 1 . 0 4 × 1 0− 4 and a female mutation rate of 5 . 1 8 × 1 0− 5 with an overall mutation rate of approximately 7 . 7 7 × 1 0− 5. Also, in this study, we found that the identified mutations are in close proximity to the center of the repeat array rather than at the ends of the repeat array. Several studies have examined the mutational mechanisms of the minisatellites according to infinite allele model (IAM) and the one-step stepwise mutation model (SMM). In this study, we found that this locus fits into the one-step mutation model (SMM) mechanism in six out of seven instances similar to STR loci.

Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Background The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. Methods Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. Results A novel heterozygous missense mutation [c.13T>G (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. Conclusions This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese.

Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons

Funding: This work was partially supported by grants from National Basic Research Program of China (2013CB530605; 2014CB942803), from National Natural Science Foundation of China 1230046; 31071252; 81101182) and from Chinese Academy of Sciences (KSCX2-EW-R-05, KJZD-EW-L08). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

A tumoral and invasive phenotype independent of c-Met mutation

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude de la biologie cellulaire du facteur autocrine de motilité et de la fibronectine

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Variable mutation rates as an adaptive strategy in replicator populations

For evolving populations of replicators, there is much evidence that the effect of mutations on fitness depends on the degree of adaptation to the selective pressures at play. In optimized populations, most mutations have deleterious effects, such that low mutation rates are favoured. In contrast to this, in populations thriving in changing environments a larger fraction of mutations have beneficial effects, providing the diversity necessary to adapt to new conditions. What is more, non-adapted populations occasionally benefit from an increase in the mutation rate. Therefore, there is no optimal universal value of the mutation rate and species attempt to adjust it to their momentary adaptive needs. In this work we have used stationary populations of RNA molecules evolving in silico to investigate the relationship between the degree of adaptation of an optimized population and the value of the mutation rate promoting maximal adaptation in a short time to a new selective pressure. Our results show that this value can significantly differ from the optimal value at mutation-selection equilibrium, being strongly influenced by the structure of the population when the adaptive process begins. In the short-term, highly optimized populations containing little variability respond better to environmental changes upon an increase of the mutation rate, whereas populations with a lower degree of optimization but higher variability benefit from reducing the mutation rate to adapt rapidly. These findings show a good agreement with the behaviour exhibited by actual organisms that replicate their genomes under broadly different mutation rates. © 2010 Stich et al.

Dysfonctions mitochondriales associées à l’acidose lactique du Saguenay-Lac-Saint-Jean révélées par l’étude d’un nouveau modèle murin de la maladie

Le syndrome de Leigh version canadienne-française (LSFC) est une maladie autosomale récessive causée par une mutation du gène LRPPRC, encodant une protéine du même nom. LRPPRC est impliquée dans la traduction des gènes mitochondriaux qui encodent certains complexes de la chaine respiratoire. Les répercussions biochimiques incluent un déficit tissu spécifique de la cytochrome c oxydase (COX), principalement dans le foie et le cerveau, et la survenue de crises d’acidose fatales chez 80 % des enfants atteints avant l’âge de 3-4 ans. L’identification d’options thérapeutiques demeure encore un défi de taille et ceci est en partie relié au manque de connaissances des fonctions biologiques de LRPPRC et des mécanismes impliqués dans la pathogenèse du LSFC, au niveau des dysfonctions mitochondriales résultantes. Afin d’étudier ces mécanismes, le consortium de l’acidose lactique, dont fait partie notre laboratoire, a récemment développé un modèle murin portant une ablation de LRPPRC spécifique au foie (souris H-Lrpprc-/-). L’objectif principal est de déterminer si ce modèle reproduit le phénotype pathologique observé dans les cultures de fibroblastes humains issus de biopsies de peau de patients LSFC. Dans le cadre des travaux de ce mémoire, nous avons amorcé la caractérisation de ce nouveau modèle, en examinant le phénotype général, l’histopathologie hépatique et les fonctions mitochondriales, et en nous focalisant principalement sur les fonctions respiratoires et la capacité à oxyder divers types de substrats. Nous avons observé un retard de croissance, une hépatomégalie ainsi que plusieurs anomalies histologiques du foie chez la souris HLrpprc-/-. De plus, l’ablation de LRPPRC induit un déficit du complexe IV, mais aussi de l’ATP synthase, et affecte l’oxydation des acides gras à longues chaines. À la lumière de ces résultats, nous croyons que le modèle murin H-Lrpprc-/- contribuera à l’avancement des connaissances générales sur LRPPRC, nous permettant de mieux comprendre l’influence de la protéine sur les fonctions mitochondriales.

A tumoral and invasive phenotype independent of c-Met mutation

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude de la biologie cellulaire du facteur autocrine de motilité et de la fibronectine

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Cinematic and Aesthetic Cartographies of Subjective Mutation

This article examines the use of cinema as a mapping of subjective mutation in the work of Deleuze, Gauttari and Berardi. Drawing on Deleuze's distinction between the reduction of the art-work to the symptom and the idea of art as symptomatology, the article focuses on Berardi's use of cinematic examples, posing the question in each case of to what extent they function as symptomatologies or mere symptoms of cultural and subjective mutations in examples ranging from Bergman's Persona to Van Sant's Elephant to finish on speculations about Fincher's The Social Network as a critical engagement with subjective mutation in the 21st Century.

Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 low-risk essential thrombocythemia patients (CALR-mutated n=271, JAK2V617F-mutated n=162) who were on antiplatelet therapy or observation only. After a 2215 person-years follow-up free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 vs. 1.8 x1000 patient-years, p=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; p=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated than in JAK2V617F-mutated essential thrombocythemia (median time 5 years and 9.8 years, respectively; p=0.0002) usually to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

Chemoprevention in BRCA1 Mutation Carriers—A Proof-of-Concept Study

Background: Women with germline BRCA1 mutations have a high lifetime risk of breast cancer, with the only available risk-reduction strategies being risk-reducing surgery or chemoprevention. These women predominantly develop triple-negative breast cancers; hence, it is unlikely that selective estrogen receptor modulators (serms) will reduce the risk of developing cancer, as these have not been shown to reduce the incidence of estrogen receptor–negative breast cancers. Preclinical data from our laboratory suggest that exposure to estrogen and its metabolites is capable of causing dna double-strand breaks (dsbs) and thus driving genomic instability, an early hallmark of BRCA1-related breast cancer. Therefore, an approach that lowers circulating estrogen levels and reduces estrogen metabolite exposure may prove a successful chemopreventive strategy.

Aims: To provide proof of concept of the hypothesis that the combination of luteinizing-hormone releasing-hormone agonists (lhrha) and aromatase inhibitors (ais) can suppress circulating levels of estrogen and its metabolites in BRCA1 mutation carriers, thus reducing estrogen metabolite levels in breast cells, reducing dna dsbs, and potentially reducing the incidence of breast cancer.

Methods: 12 Premenopausal BRCA1 mutation carriers will undergo baseline ultrasound-guided breast core biopsy and plasma and urine sampling. Half the women will be treated for 3 months with combination goserelin (lhrha) plus anastrazole (ai), and the remainder with tamoxifen (serm) before repeat tissue, plasma, and urine sampling. After a 1-month washout period, groups will cross over for a further 3 months treatment before final biologic sample collection. Tissue, plasma, and urine samples will be examined using a combination of immunohistochemistry, comet assays, and ultrahigh performance liquid chromatography tandem mass spectrometry to assess the impact of lhrha plus ai compared with serm on levels of dna damage, estrogens, and genotoxic estrogen metabolites. Quality of life will also be assessed during the study.

Results: This trial is currently ongoing.

p.(L576P) -KIT mutation in GIST: Favorable prognosis and sensitive to imatinib?

Exon 11 KIT mutations are found in a majority of gastrointestinal stromal tumors (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favorable response to imatinib and outcome in 5 p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy.