Caractérisation clinique et génétique d'une nouvelle forme de dystrophie musculaire avec hyperlaxité

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

Études de nouvelles maladies neurogénétiques chez les Canadiens français

Depuis déjà plusieurs décennies, nous sommes en mesure d'identifier les mutations responsable de diverses maladies mendéliennes. La découverte des gènes responsables de ces maladies permet non seulement un meilleur diagnostic clinique pour ces familles, mais aussi de mieux comprendre les mécanismes physiopathologiques de ces maladies ainsi que mieux définir la fonction normale des gènes causales. Ultimement, ces découvertes mènent à l'identification de cibles thérapeutiques pour le traitement de ces maladies. Les progrès technologiques sont depuis toujours un facteur très important dans la découverte de ces gènes mutés. De l'approche traditionnelle de clonage positionnel en passant par la première séquence du génome humain et maintenant les technologies de séquençage à grande échelle, de plus en plus de maladies ont maintenant une entité génétique. Dans le cadre de ce projet de doctorat, nous avons utilisé tant les approches traditionnelles (leucodystrophies) que les nouvelles technologies de séquençage (polyneuropathie douloureuse) qui ont mené à l'identification du gène causal pour plusieurs de nos familles. L'efficacité de ces deux approches n'est plus à démontrer, chacune d'entre elles possèdent des avantages et des inconvénients. Dans le cadre de ces projets, nous avons utilisé la population canadienne-française connue pour ces effets fondateurs et la présence, encore aujourd'hui, de grandes familles. Les différents projets ont permis d'établir certains avantages et inconvénients quant à l'utilisation de ces techniques et de la population canadienne-française. Dans le cadre d'un phénotype assez homogène et bien défini comme celui du projet leucodystrophie, l'approche traditionnel par gène candidat nous a permis d'identifier le gène causal, POLR3B, sans trop de difficulté. Par contre, pour les autres projets où nous sommes en présence d'une hétérogénéité clinique et génétique une approche non-biaisée utilisant le séquençage exomique a obtenu un plus grand succès. La présence de grandes familles est un grand avantage dans les deux approches. Dans le projet polyneuropathie douloureuse, une grande famille originaire du Saguenay-Lac-St-Jean nous a permis d'identifier le gène NAGLU comme responsable suite à l'exclusion des autres variants candidats par analyse de ségrégation. Comme NAGLU était déjà associé à un phénotype qui diffère sur plusieurs points à celui de notre famille, une approche traditionnelle n'aurait pas été en mesure d'identifier NAGLU comme le gène causal. Dans l'analyse de nos données de séquençage exomique, nous avons observé que plusieurs variants rares, absents des bases de données, étaient partagés entre les différents individus Canadiens français. Ceci est probablement dû à la démographie génétique particulière observée chez les Canadiens français. En conclusion, les technologies de séquençage à grande échelle sont avantageuses dans l'étude de maladies hétérogènes au niveau clinique et génétique. Ces technologies sont en voie de modifier l'approche d'identification de gènes en permettant une analyse de génétique inversée, c'est-à-dire de la génétique vers la clinique.Since many decades we are able to identify mutations responsible for Mendelian diseases. The identification of the causative gene not only allows a better diagnostic to these families, but also allows a better understanding of the pathophysiological mechanisms of these disorders and of the normal function of a gene. Ultimately, those discoveries lead to the identification of therapeutic targets that will enable clinicians to treat these diseases. Technological progress has forever driven gene identification. Starting with traditional approaches like positional cloning passing through the first sequence of the human genome and finally the recent high-throughput sequencing technologies, more and more diseases are now linked to a genetic cause. During my PhD, I had the opportunity to use traditional approaches (leukodystrophy) as well as new sequencing technologies (painful sensory polyneuropathy) which both led to gene identification for some of our families. The efficiency of these approaches is well known, each of them has advantages and disadvantages. In these projects, we used the french-canadian population well known for its founder effect and the presence, still today, of large families. Working on these projects allowed us to establish advantages and disadvantages concerning the use of those technologies and the french-canadian population. In the presence of a homogenous and well defined phenotype, like the leukodystrophy project, the traditional approach enables us to rapidly identify the causative gene (POLR3B). On the other hand, the unbiased exome sequencing approach has had more success for diseases characterized with clinical and genetic heterogeneity. Large families are a great advantage for both methods. In the painful sensory polyneuropathy project, a large family originated from the Saguenay-Lac-St-Jean region allowed us to identify the NAGLU gene as responsible for the disease after exclusion of the candidate variants by segregation analysis. NAGLU has already been associated with a phenotype that differs in many points with the clinical features observed in our family. In this case a traditional approach would have failed to identify NAGLU as the causative gene. In the analysis of our exome sequencing results, we observed many rare variants absent from databases but shared between french-canadian individuals. This enrichment in rare variants is probably due to the particular genetic demography of Quebec. In conclusion, high-throughput sequencing technologies are advantageous in the study of clinically and genetically heterogeneous diseases. These technologies are changing the gene identification approach towards reverse genetics, meaning genetics towards clinic

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Intercultural Experiences Prior to the Educational Program: Occupational Therapy and Social Work Students

In the health and social professions, including occupational therapy and social work, interactions and exchanges with people are essential. Populations encountered by professionals in these fields are becoming increasingly diverse in terms of age, origin, language, health status, and socio-economic background. Sometimes, professionals can have potential misinterpretations regarding intentions and actions, health beliefs and practices, or verbal and non-verbal communication. To overcome obstacles related to practice in a context of diversity, universities must develop students’ intercultural competence. Scientific literature stresses the importance of encountering diversity to improve awareness and sensitivity and to bring attention to biases and prejudices. Considering students’ intercultural experiences before their formation could be a basis to achieve this educational goal. The present study aims to document this topic. Semi-structured interviews with 51 first-year students from two educational institutions in French-speaking Switzerland were conducted to capture the participants’ descriptions of these experiences in private or professional contexts. The interviews were transcribed and submitted to a thematic analysis approach. A thematic map was generated and three main themes emerged: (1) perception of diversity; (2) communication challenges; and (3) transformation of attitudes toward the “Other.” They are described and discussed in terms of developing intercultural competence. Recommendations regarding intercultural education emerge from these findings

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair1,2. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP3,4,5 and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease

Mutations in LAMA1 Cause Cerebellar Dysplasia and Cysts with and without Retinal Dystrophy

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes

Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion

Congenital myopathies define a heterogeneous group of neuromuscular diseases with neonatal or childhood hypotonia and muscle weakness. The genetic cause is still unknown in many patients, precluding genetic counselling and better understanding of the physiopathology. To identify novel genetic causes of congenital myopathies, exome sequencing was performed in three consanguineous families. We identified two homozygous frameshift mutations and a homozygous nonsense mutation in the mitogen-activated protein triple kinase ZAK. In total, six affected patients carry these mutations. Reverse transcription polymerase chain reaction and transcriptome analyses suggested nonsense mRNA decay as a main impact of mutations. The patients demonstrated a generalized slowly progressive muscle weakness accompanied by decreased vital capacities. A combination of proximal contractures with distal joint hyperlaxity is a distinct feature in one family. The low endurance and compound muscle action potential amplitude were strongly ameliorated on treatment with anticholinesterase inhibitor in another patient. Common histopathological features encompassed fibre size variation, predominance of type 1 fibre and centralized nuclei. A peculiar subsarcolemmal accumulation of mitochondria pointing towards the centre of the fibre was a novel histological hallmark in one family. These findings will improve the molecular diagnosis of congenital myopathies and implicate the mitogen-activated protein kinase (MAPK) signalling as a novel pathway altered in these rare myopathies

Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

The study of Drosophila neurodegenerative mutants combined with genetic and biochemical analyses lead to the identification of multiple complex mutations in 60 patients with a novel form of ataxia/leukoencephalopathy

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Réseau OHS ::vers des collaborations francophones sur les occupations humaines et la santé

Les sciences de l’occupation se développent de manière continue depuis plusieurs dizaines d’années dans les pays anglo-saxons. Leur diffusion dans les pays francophones reste malheureusement plutôt faible et très inégale. Par ailleurs, elles influencent surtout les pratiques d’enseignement et dans une moindre mesure seulement les pratiques cliniques et la recherche. La Haute École spécialisée de Suisse occidentale (HES-SO) à Lausanne a récemment créé un réseau dédié à l’occupation humaine et la santé. Il vise à soutenir le développement des connaissances sur les liens entre la santé, les occupations humaines et la participation sociale, en Suisse et dans d’autres régions francophones. Il contribue également au développement d’activités de recherches appliquées, d’échanges et de formations dans ce domaine fondamental pour les ergothérapeutes. Mais au-delà de ses activités, il veut établir des ponts ainsi que formaliser les collaborations entre ergothérapeutes francophones d’Europe, d’Amérique du Nord, d’Afrique du Nord et demain, qui sait, des autres continents.In many English-speaking countries and since several decades Occupational science is in continuous development. The situation is very different in French-speaking countries where the diffusion of Occupational science varies widely. Thus, Occupational science influences mainly academic practice and only to a lesser degree clini- cal practice. The University of Applied Sciences and Arts of Western Switzerland recently launched a network dedicated to human occupa- tion and health (OHS). It is intended to support the development of knowledge on occupation, health and social participation in the French- speaking part of Switzerland, and in other French speaking areas. It will develop applied research activities and contribute to knowledge exchange in this domain. In addition to these activities, OHS will also contribute to build bridges between French speaking professionals in Europe, in North America, in North Africa and, maybe, also other continents