Дисертації з теми "LGMDR8"
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Kirk, Calum Norman Robert. "Pathophysiology of anoctaminopathy (LGMD2L)." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3861.
Повний текст джерелаBritton, Stephen Andrew. "Characterisation of expressed sequences from LGMD2B region of chromosome 2p13." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311106.
Повний текст джерелаRichard, Isabelle. "Etiologie moleculaire de la dystrophie musculaire des ceintures type 2a (lgmd2a)." Paris 7, 1996. http://www.theses.fr/1996PA077273.
Повний текст джерелаBawa, Simranjot. "Exploring the molecular mechanisms of Drosophila dTRIM32 implicated in pathogenesis of Limb-Girdle Muscular Dystrophy 2H." Thesis, Kansas State University, 2017. http://hdl.handle.net/2097/38243.
Повний текст джерелаBiochemistry and Molecular Biophysics Interdepartmental Program
Erika Rae Geisbrecht
The E3 ubiquitin ligase TRIM32 is a member of tripartite motif (TRIM) family of proteins involved in various processes including differentiation, cell growth, muscle regeneration and cancer. TRIM32 is conserved between vertebrates (humans, mouse) and invertebrates (Drosophila). The N-terminus of this protein is characterized by a RING domain, B-box domain, and Coiled-Coil region, while the C-terminus contains six NHL repeats. In humans, mutations that cluster in the NHL domains of TRIM32 result in the muscle disorders Limb-Girdle Muscular Dystrophy type 2H (LGMD2H) and Sarcotubular Myopathy (STM). Mutations in the B-box region cause Bardet-Biedl Syndrome (BBS), a clinically separate disorder that affects multiple parts of the body. A comprehensive genetic analysis in vertebrate models is complicated by the ubiquitous expression of TRIM32 and neurogenic defects in TRIM32-/- mutant mice that are independent of the muscle pathology associated with LGMD2H. The model organism Drosophila melanogaster possesses a TRIM32 [dTRIM32/Thin (Tn)/Abba] homolog highly expressed in muscle tissue. We previously showed that dTRIM32 is localized to Z-disk of the sarcomere and is required for myofibril stability. Muscles form correctly in Drosophila tn mutants, but exhibit a degenerative muscle phenotype once contraction ensues. Mutant or RNAi knockdown larvae are also defective in locomotion, which mimics clinical features associated with loss of TRIM32 in LGMD2H patients. It is predicted that mutations in the NHL domain either affect protein structure or are involved in protein-protein interactions. However, the molecular mechanism by which these mutations affect the interaction properties of dTRIM32 is not understood. Biochemical pulldown assays using the bait fusion protein GST-dTRIM32-NHL identified numerous dTRIM32 binding proteins in larval muscle tissue. Many key glycolytic enzymes were present in the dTRIM32 pulldowns and not in control experiments. Glycolytic genes are expressed in the developing Drosophila musculature and are required for myoblast fusion. Strikingly, many glycolytic proteins are also found at the Z-disk, consistent with dTRIM32 localization. Our biochemical and genetic studies provide evidence that there is direct interaction between dTRIM32 and glycolytic proteins (Aldolase and PGLYM). dTRIM32 also regulates glycolytic enzyme levels and protein localization at their sites of action. These data together suggest a role for dTRIM32 in coordinating glycolytic enzyme function, possibly for localized ATP production or to maintain muscle mass via glycolytic intermediates.
Rathgeber, Matthew F. "Galectin-1 Improves Sarcolemma Repair and Decreases the Inflammatory Response in LGMD2B Models." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8723.
Повний текст джерелаTaveau, Mathieu. "Caractérisation de la fonction et du mécanisme d'activation de la calpaïne 3, une protéase musculaire déficiente dans la dystrophie des ceintures de type 2A." Paris 6, 2003. http://www.theses.fr/2003PA066315.
Повний текст джерелаFOUGEROUSSE, FRANCOISE. "Cartographie d'une region genetique impliquee dans la dystrophie musculaire des ceintures (lgmd2)." Paris 7, 1994. http://www.theses.fr/1994PA077140.
Повний текст джерелаMonjaret, François. "Evaluation de trois approches de thérapie génique pour le traitement des dysferlinopathies : miniprotéine, compensation et trans-épissage." Thesis, Evry-Val d'Essonne, 2012. http://www.theses.fr/2012EVRY0035/document.
Повний текст джерелаDysferlinopathies are muscular diseases due to mutations in DYSF gene, inducing dysferlin protein deficiency. In this thesis, three therapeutic approaches have been investigated for these pathologies, on cell or mice models. A short transcriptional dysferlin variant has been injected into Bla/J dysferlin deficient mouse model, using AAV8r vector. Muscle fibers of treated animals displayed an increased resistance to mechanical stress without therapeutic benefit. These experiments also pointed out the toxicity of this strategy. A protein compensation approach has been tested using anoctamin 5, known to be involved in pathologies and activities similar to dysferlin’s ones. AAVr mediated Anoctamin 5 overexpression in Bla/J model does not rescue their muscle phenotype. Overexpression of ANO5 does not seem to be a valuable therapeutic strategy for dysferlin deficiency. Dysferlin RNA surgery was evaluated as a possible genetic therapy using Spliceosome-Mediated RNA Trans-splicing (SMaRT). On a Minigene target, SMaRT is able to induce RNA reprogramming by trans-splicing, and produce the corresponding protein. But efficiency is by far decreased in endogenous context and not good enough to restore functional dysferlin in human myoblasts. Moreover, we described proteins resulting from RNA-trans-splicing molecule (RTM) self-expression, limiting the value of SMaRT as therapeutic strategy, especially for dysferlinopathies
Broux, Odile. "Localisation, identification et etude d'un gene responsable d'une forme autosomique recessive de dystrophie musculaire de ceintures (lgmd2e)." Littoral, 1997. http://www.theses.fr/1997DUNK0008.
Повний текст джерелаAllamand, Valérie. "Cartographie genetique fine de la region impliquee dans une forme autosomique recessive de dystrophie musculaire des ceintures (lgmd2a)." Paris 7, 1995. http://www.theses.fr/1995PA077002.
Повний текст джерелаPANICUCCI, CHIARA. "The role of inflammation on disease progression in alpha-sarcoglycan-related limb girdle muscular dystrophy (LGMDR3): new insights from human histological analysis and in vivo studies on Sgca-null mice." Doctoral thesis, Università degli studi di Genova, 2022. http://hdl.handle.net/11567/1080120.
Повний текст джерелаPetersen, Jens A. "Klinische und molekulare Charakterisierung von Patienten mit Gliedergürteldystrophie 2I (LGMD 2I)." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-37620.
Повний текст джерелаMalcher, Jakub. "Exon skipping as a therapeutic strategy in dysferlinopathy." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLV007.
Повний текст джерелаDysferlinopathy is a muscular dystrophy that manifests as two major phenotypes: limb-girdle muscular dystrophy type 2B (LGMD2B) or Miyoshi myopathy (MM). It is caused by mutations in the dysferlin gene. Dysferlin is a membrane protein expressed in skeletal muscle. It is responsible for the repair of sarcolemma microlesions produced by muscle contractions. A compromised membrane repair leads to slowly progressing muscle wasting. This thesis explores the therapeutic potential of an antisense mediated splice switching strategy in LGMD2B caused by the missense mutation c4022T>C in the exon 38 of the dysferlin gene. Antisense oligonucleotides and U7 snRNAs delivered by an adeno-associated viral vector were used as antisense tools to trigger exon skipping in vitro and in vivo. The thesis investigates also if the truncated dysferlin maintainsa proper membrane localization and its membrane repair ability
Soardi, Michela. "Generation of novel zebrafish models of sarcoglycanopathy." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3426362.
Повний текст джерелаLe sarcoglicanopatie sono quattro rare patologie autosomiche recessive appartenenti alla famiglia delle distrofie muscolari di tipo 2 (LGMD2C-F). Esse sono causate da mutazioni nei geni SGCG, SGCA, SGCB, SGCD codificanti rispettivamente per γ-, α-, β- e δ- sarcoglicano (SG). I SG formano un complesso tetramerico nel sarcolemma, connesso a quello delle glicoproteine associate alla distrofina (DAPC), essenziale per garantire l'integrità della membrana durante la contrazione muscolare (Bushby, 2009). Mutazioni dei SG causano la perdita/riduzione della proteina mutata e dei partner wild type (WT), alterando le proprietà strutturali del DAPC e aumentando la fragilità del sarcolemma. La maggior parte delle mutazioni sono di tipo missenso e, causando un problema nel folding, portano alla prematura degradazione della proteina mutata effettuata dalla via ERAD (degradazione associata al reticolo endoplasmatico) attraverso il proteasoma (Gastaldello et al., 2008; Bartoli et al., 2008). La conoscenza del meccanismo patologico ha aperto nuove strade a due possibili interventi farmacologici: inibendo la degradazione o assistendo il processo di folding dei mutanti, il complesso dei SG è recuperato riducendo così la fragilità della membrana (Bianchini et al., 2014; Carotti et al., 2018). Questi dati prodotti in vitro suggeriscono che molti mutanti sono ancora funzionali, sebbene strutturalmente difettosi. Tuttavia, per la messa a punto di un approccio terapeutico, questi dati necessitano di una validazione in vivo, attraverso modelli animali per mimare la malattia umana e recanti quindi mutazioni missenso nei SG. In assenza di modelli murini, un’alternativa promettente per lo studio di molte malattie, fra cui i disturbi muscolari, è rappresentata dallo zebrafish (D.rerio). Tra gli ortologhi dei SG umani, β- e δ-SG sono i più conservati e quindi sono stati scelti per produrre linee knock-out (KO) e knock-in (KI). La bontà dell’uso di questo vertebrato nel mimare la sarcoglicanopatia nasce da uno studio preliminare di Knock-Down con morfolino contro il δ-SG. I morfanti ottenuti hanno mostrato: alterazioni morfologiche, danni alla struttura muscolare e compromissione delle capacità motorie. Grazie a queste premesse, il sistema CRISPR/Cas9 è stato usato per generare modelli KO di β- e δ-SG. In entrambi i casi, l'assenza della proteina provoca la progressiva alterazione della struttura muscolare e delle capacità motorie. Attualmente stiamo usando i KO come background per l'iniezione della sequenza WT o mutata dei SG, sia di origine umana sia di zebrafish. La prima dovrebbe consentire il recupero del fenotipo, mentre quella delle forme mutate permetterà di valutare la capacità dello zebrafish di riconoscerle e degradarle. Questi esperimenti sono della massima importanza per verificare l'idoneità dello zebrafish nel mimare le forme di sarcoglicanopatia causate da mutazioni missenso. La generazione di due modelli KI in zebrafish, β-SGT145R/T145R e δ-SGE264K/E264K, prevede l’attivazione della via di riparazione HDR (riparazione omologa diretta). Poiché l'efficienza della ricombinazione omologa è molto bassa, è necessario l’uso di un metodo altamente selettivo per identificare i pesci positivi alla voluta mutazione. Lo screening delle mutazioni somatiche per l'introduzione della mutazione T145R nel gene z-sgcb è stato positivo. Attualmente stiamo aspettando la maturazione sessuale della popolazione F0 per identificare quei pesci in cui ricombinazione sia avvenuta nella linea germinale. Se le linee KI, una volta caratterizzate, mimeranno la patologia umana, rappresenteranno uno strumento fondamentale per testare l'approccio farmacologico proposto in vitro, e costituiranno un valido stimolo per la ricerca di base e traslazionale.
Aho, Anna Carin. "Living with recessive limb-girdle muscular dystrophy : affected young adults’ and parents’ perspectives, studied througha salutogenic framework." Doctoral thesis, Linnéuniversitetet, Institutionen för hälso- och vårdvetenskap (HV), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-68737.
Повний текст джерелаFritegotto, Chiara. "Indagini genetiche, molecolari e traslazionali in diverse forme di distrofie muscolari." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3424084.
Повний текст джерелаLa Distrofia Miotonica (DM) è la più comune forma di distrofia muscolare nell’adulto. In particolare un’espansione della tripletta CTG nella regione 3’UTR del gene DMPK (myotonic dystrophy protein kinasi) è causativa della distrofia miotonica di tipo 1 (DM1; MIM# 160900), una malattia a trasmissione autosomica dominante, multisistemica che coinvolge diversi apparati del corpo umano come il sistema endocrino, il cuore, i muscoli scheletrici, oculari, il cervello. La DM1 presenta forme congenite e il coinvolgimento del sistema nervoso centrale. I microRNA sono corte molecole di RNA a singolo filamento non codificanti, in grado di regolare l’espressione genica a livello post trascrizionale. Sono coinvolti in molti processi biologici, come lo sviluppo embrionale, il differenziamento e la proliferazione cellulare. Esistono dei microRNA espressi a livello muscolare (myomiRs), in particolare il miR-1 e il miR133a/b, espressi nel muscolo scheletrico e cardiaco, e il miR-206, espresso nel muscolo scheletrico. L’obiettivo principale è di studiare il profilo di espressione di questi microRNA nel muscolo scheletrico e nel siero di pazienti affetti da distrofia miotonica di tipo 1. I risultati dello studio nel muscolo hanno mostrato una diminuzione di miR-1 e miR-133a nei pazienti DM1 rispetto ai controlli, miR-133b non mostra significative variazioni, mentre miR-206 aumenta significativamente nel muscolo di pazienti DM1. Questi dati sono stati confrontati con la valutazione semiquantitativa del grado di compromissione istopatologico delle biopsie muscolari, senza però trovare una correlazione tra alterazione dell’espressione dei microRNA e compromissione del muscolo. Si sono indagati i livelli dei microRNA nel siero di pazienti DM1 prima e dopo un periodo di riabilitazione, allo scopo di comprendere il ruolo di queste molecole a livello muscolare e in particolare il loro coinvolgimento in processi di ipertrofia e rigenerazione muscolare. Le analisi svolte sul siero al tempo zero (ingresso all’ospedale) evidenziano una diminuzione nell’espressione di miR-1, miR-133b e miR-206 rispetto ai controlli, al contrario miR-133a mostra un livello di espressione più elevato. Dopo trattamento riabilitativo (tempo 1) c’è un abbassamento significativo di tutti e quattro i microRNA analizzati
Cheng, Hsien-Wen, and 鄭獻文. "Mutation analysis of the DYSF gene in LGMD2B patients using DHPLC." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/11749899776360155422.
Повний текст джерела高雄醫學大學
醫學研究所碩士班
95
Dysferlin(DYSF) gene encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B(LGMD 2B), the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF gene. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 11 unrelated LGMD 2B patients, including 7 suspected LGMD 2B Taiwanese patients, and 4 Japanese patients with 6 confirmed mutations in DYSF gene. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using denaturing high performance liquid chromatography(DHPLC)of PCR products of each of 55 exons of the gene was followed by sequencing whenever a variation was detected. In 7 Taiwanese patients, 17 sequence variations were identified in DYSF, 3 of which predict single amino-acid substitution and are novel, while the other 14 changes are known SNPs (Single nucleotide polymorphisms). The three novel sequence variations, G486、A3472G、C334T, was not detected in 150 normal individuals and was identified as potential pathogenic mutation (SNP<1%). These three mutations were widely spread in the coding sequence of the gene.
Heng, Yi. "The role of TRIM32 in Limb-Girdle Muscular Dystrophy type 2H (LGMD2H)." 2008. http://hdl.handle.net/1993/21282.
Повний текст джерелаPetersen, Jens [Verfasser]. "Klinische und molekulare Charakterisierung von Patienten mit Gliedergürteldystrophie 2I (LGMD 2I) / vorgelegt von Jens Alexander Petersen." 2005. http://d-nb.info/976070391/34.
Повний текст джерелаFrosk, Patrick. "Limb girdle muscular dystrophy in the Hutterite population of Manitoba." Thesis, 2006. http://hdl.handle.net/1993/249.
Повний текст джерелаMay 2005
Monteiro, Isabel Rovisco Correia Gonçalves. "Disferlinopatias: heterogeneidade clínica, genética e prognóstico funcional em quinze doentes." Master's thesis, 2017. http://hdl.handle.net/10316/82370.
Повний текст джерелаIntrodução: As disferlinopatias são doenças musculares de transmissão autossómica recessiva provocadas por mutações no gene da disferlina (DYSF). Os fenótipos mais comuns são a Miopatia de Myoshi (MM) e a Distrofia Muscular das Cinturas 2B (DMC 2B).Objectivos: Descrever as características clínicas, laboratoriais, moleculares e a evolução clínica de quinze doentes com disferlinopatia.Metodologia: Registaram-se dados demográficos, clínicos, laboratoriais e moleculares de quinze doentes com diagnóstico de disferlinopatia. Foi avaliada a marcha, existência de sintomatologia cardiorrespiratória e resultados de electrocardiograma, provas de função respiratória e radiografia torácica.Resultados: Quinze doentes (oito do género masculino), com idade média actual de 47+/-16 anos. A idade média dos primeiros sintomas foi 24+/-14 anos e o tempo médio até ao diagnóstico molecular de 12+/-12 anos. Na observação inicial, o fenótipo DMC 2B observou-se em oito doentes, o de MM em três, hipercreatinémia (hiperCK) isolada em dois, proximodistal num doente e Miopatia Distal do Compartimento Anterior (MDCA) noutro doente. Atualmente, oito doentes apresentam generalização da fraqueza muscular (um DMC 2B e sete proximodistais) e sete doentes mantêm o fenótipo inicial (quatro DMC 2B, um hiperCK, um MDCA, um proximodistal). No momento do diagnóstico, todos os doentes tinham marcha autónoma, sendo que nove perderam capacidade de marcha e três fazem atualmente marcha com apoio (tempo médio até perda de marcha autónoma de 17+/-9 anos). Sete doentes referiram dispneia e/ou ortopneia. 18% das radiografias torácicas apresentaram aumento do índice cardiotorácico (ICT) e foram encontradas anomalias em 50% das provas de função respiratória (PFR) e 54% dos electrocardiogramas (ECG). Valores séricos de creatina quinase (CK) estavam elevados em todos os doentes. Observaram-se treze mutações diferentes no gene DYSF, dez em homozigotia e cinco em heterozigotiaConclusões: O reconhecimento da heterogeneidade fenotípica e molecular e da evolução clínica das disferlinopatias evidenciada nesta série poderá contribuir para o diagnóstico mais precoce e dirigido desta doença.
Introduction: Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene (DYSF). Dysferlin deficiency leads to several phenotypes, with Myoshi Myopathy (MM) and Limb Girdle Muscular Dystrohy 2B (LGMD 2B) being the most common ones. Aim: Describe the clinical, laboratorial and molecular findings of fifteen patients with muscle disease caused by pathogenic mutations in the DYSF gene, as well as the progression of the disease. Methods: A total of fifteen patients with molecular confirmed dysferlinopathy were clinical and laboratory assessed. The initial and actual pattern of muscle weakness, the gait, the rate of progression and distribution of the muscle weakness, the presence of cardiorespiratory symptoms and the results of electrocardiogram, thoracic radiography and respiratory function were evaluated. Results: Fifteen patients (eight males) with a mean age at the present evaluation of 47±16 years old. The mean age of onset of the disease was 24±14 years and the mean time until the molecular confirmation was 12±12 years. At the initial evaluation, five different phenotypes were identified: eight patients with LGMD2B, three with MM, two with HiperCK, one with proximodistal phenotype (Mixed type) and one with distal anterior compartment myopathy (DACM). At the last clinical evaluation, eight of them presented generalization of the weakness (one LGMD2B and seven proximodistal phenotype) and seven maintained their initial phenotype (four LGMD2B, one hiperCK, one DACM and one proximodistal). At the first clinical examination, all patients were able to walk without support and presently nine became wheelchair-bound and three needed walking assistance (mean time to loss of autonomous walk of 17 ±9 years). Seven patients referred dyspnea and/or orthopnea. 18% of thoracic x-rays presented an enlargement of the cardiothoracic index and abnormalities were found in 50% of the respiratory function tests and in 54% of the electrocardiograms. All patients had elevated serum creatine kinase (CK) levels. Thirteen sequence variations were identified in DYSF gene. Ten patients carried a single homozygous mutation; five patients had two compound heterozygous mutations. Conclusions: Dysferlinopathies are clinical and genetic heterogeneous muscle diseases with progression in the majority of the patients. The recognition of this features evidenced in this series, may contribute to the earlier and directed diagnosis of this disease.
Bolduc, Véronique. "Identification du gène Anoctamine 5 responsable d'une nouvelle forme récessive de dystrophie musculaire des ceintures." Thèse, 2011. http://hdl.handle.net/1866/6316.
Повний текст джерелаLimb-girdle muscular dystrophies (LGMD) encompass a broad spectrum of muscular dystrophies in which the initial weakness arises in proximal muscles. We previously described in French-Canadian (FC) families a new form of LGMD characterized by asymmetrical quadriceps femoris atrophy, named LGMD2L, which we mapped to chromosome 11p12-p13 using linkage analyses. The objectives of this thesis project were to refine the candidate interval, identify and characterize the LGMD2L gene. Using single nucleotide polymorphisms (SNPs) homozygosity mapping in a large consanguineous family, we narrowed down the LGMD2L candidate interval to a region on chromosome 11p14.3-p15.1, and identified three mutations in the Anoctamin 5 (ANO5) gene located in the interval. These mutations consisted of a missense, a one-bp duplication and a splice site mutation. We demonstrated that the latter two triggered the nonsense-mediated RNA decay pathway. In addition, we identified ANO5 mutations in cases affected by a non-dysferlin Miyoshi muscular dystrophy mapped also to chromosome 11, termed MMD3. In two MMD3 families of European descent, patients presented with calf weakness as the initial symptoms, sometimes evolving to quadriceps atrophy. Fibroblasts from one MMD3 family were shown to be defective for membrane repair. ANO5 localization and function in muscle are unknown, but it is a member of the conserved Anoctamin family of proteins with eight transmembrane domains, of which some function as calcium-activated chloride channel. Our immunofluorescence studies on longitudinal muscle sections suggest that ANO5 is not importantly localized to the sarcolemma, but rather to a structure following the Z-line. To our surprise, this localization was preserved for a LGMD2L patient homozygous for the splice site mutation, previously considered as a null mutation. By studying the splicing isoforms in this patient, we observed that skipping of exon 15 occurs on a proportion of transcripts, in addition to the aberrant splicing caused by the mutation. This alternative splicing event would recover the reading frame, thus underlining the complexity of ANO5 splicing and suggesting that LGMD2L could be the consequence of a partial, rather than complete, loss-of-function. Subsequent studies by other groups have shown that anoctaminopathies 5 are a common cause of adult-onset LGMD. Our discovery of ANO5 mutations has shed light on a new class of proteins important for the muscle biology and opened new research avenues to study how defective membrane repair progresses into muscular dystrophies.