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Cao, Michelangelo (2018) Facio-scapulo-humeral dystrophy: clinical follow-up and role of chromosome X inactivation in female patients - SHP2: a novel therapeutic target in MuSK-myasthenia. [Ph.D. thesis]

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Abstract (english)

Part I. Facio-scapulo-humeral dystrophy: clinical follow-up and role of chromosome X inactivation in female patients.
Facio-scapulo-humeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy characterized by high prevalence and clinical variability. It involves facial muscles, shoulder girdle and, in most severe cases, the lower limbs. Over 95% of patients have a contraction of D4Z4 repeated units on chromosome 4q35 that causes hypomethylation of the region and the overexpression of a toxic factor, DUX4. In about 5% of patients, called FSHD2, D4Z4 hypomethylation is due to mutations of SMCHD1, a gene involved in the inactivation of chromosome X during embryotic development. The aim of this study was to evaluate the clinical progression of FSHD over a 5-year follow-up using the Clinical Severity Score (CSS), a scale previously validated by the Italian Network for FSHD. Furthermore, considering the role of SMCHD1 in the epigenetic control of the chromosome X and the differences in severity between genders, the inactivation pattern of the chromosome X was analysed in order to test whether it could represent a genetic modifier of the disease.
The sample consisted of 55 FSHD patients (29 males and 26 females) from the Neuromuscular Centre of Padova. All subjects carried a pathological D4Z4 fragment between 17-40 Kb. Patients who had been evaluated with CSS at T0 were re-evaluated after an average period of 5 years (T1). The score of each muscle region, the total CSS and the MRC score were recorded and compared between T0 and T1.
Chromosome X inactivation was analysed in 38 FSHD1 and 4 FSHD2 females measuring the degree of methylation of the CAG repeated sequence of the androgen receptor gene. Genomic DNA was digested with methylation-sensitive restriction enzymes (HpAII and HhAI), amplified by PCR and finally genotyped. 48 healthy individuals were studied as controls and X inactivation patterns were correlated to muscle impairment measured by CSS.
After 6 years of follow-up, the mean CSS difference between T0 and T1, and MRC score at biceps, triceps and tibialis anterior reached significance only in the probands group. There was no difference at shorter follow-up times or between relatives. Disease progression appeared independent of the size of D4Z4 fragment and no differences were found between genders. X-inactivation pattern was normally distributed in patients and controls. There was a moderate linear correlation between the percentage of X-inactivation and the severity of the shoulder girdle involvement, but not with any other muscle groups.
In conclusion, FSHD symptoms progress slowly over time and, although CSS represents a valuable tool for patient assessment, it lacks sensitivity for the detection of subtle clinical modifications even over a five-year period. Therefore, its use in follow-up appears to be limited. Moreover, the X inactivation pattern in FSHD patients mirrors the normal distribution observed in healthy females and correlates only modestly with the severity of the disease. These latter findings suggest that different genetic regulators are involved in the full phenotypic expression of the disease, and make evaluation of potential therapies difficult.

Part II. SHP2: a novel therapeutic target in MuSK-myasthenia.
Muscle Specific Kinase antibody myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to widespread muscle weakness and fatigability. Under physiological conditions, agrin activates the LRP4-MuSK complex, initiating a phosphorylation cascade that culminates with the clustering of acetylcholine receptors (AChRs). SH2 domain-containing phosphatase (SHP2) is a negative regulator of AChR clustering that inhibits MuSK phosphorylation. In MuSK-MG, (auto)antibodies against MuSK, mainly of the IgG4 subclass, block MuSK interaction with LRP4 and, therefore, its activation. The smaller population of MuSK IgG1-3 appear to act by a different mechanism. Although MuSK-MG is a treatable disease, a therapy that targets specifically its pathogenic mechanisms is still not available. The aim of this study was to confirm and extend preliminary findings that demonstrated the in vitro effects of a specific SHP2 inhibitor, NSC-87877, as a potential specific treatment for MuSK-MG.
Total IgG and IgG subclasses (IgG1-3, IgG4) were purified from plasma of 3 MuSK-MG patients. MuSK-Ab titres were measured by radioimmunoassay. To test the effects of NSC-87877 on MuSK phosphorylation and AChR clustering, C2C12 myotubes were used. The myotubes were incubated with increasing concentrations of NSC-87877 at different time intervals (from 15 to 360 minutes) using agrin and DMEM as positive and negative controls respectively. To test whether the drug was able to reverse the pathogenic effects of MuSK-Abs, myotubes were then exposed to agrin either with MuSK total IgG, IgG1-3 or IgG4, in the presence or absence of NSC-87877. MuSK expression and tyrosine phosphorylation were detected by western blotting, and the phosphorylation expressed as the ratio of the densitometry values of phospho-tyrosine MuSK to total MuSK. For AChR cluster quantification, myotubes were labelled with α-bungataroxin-594 followed by image acquisition and analysis with ImageJ software. For all experiments 20 images were scanned, coded, and the number of clusters > 5 μm counted using ImageJ.
In the absence of agrin, NSC-87877 caused a dose-dependent increase in both MuSK phosphorylation and AChR clustering, reaching a maximum at 100 μM, after 40 minutes of incubation. 100 μM NSC-87877 enhanced MuSK phosphorylation in the presence of MuSK total IgG and purified IgG4 while no significant change was observed with purified IgG1-3. Nevertheless, MuSK total IgG and both subclass fractions caused the dispersal of AChR clusters (see also Koneczny et al, 2013), and NSC-87877 was able to reverse their pathological effects in all samples.
SHP2 inhibition by NSC-87877 induced MuSK phosphorylation and increased AChR clustering regardless of direct stimulation by agrin. Moreover, NSC-87877 effectively induced MuSK activation despite the inhibitory effects of MuSK IgG4 antibodies, and enhanced AChR clustering in the presence of all the different IgG subclasses. Therefore, irrespectively of the MuSK IgG subclass, SHP2 inhibition represents a potential therapeutic strategy in MuSK myasthenia and further studies should access its efficacy and reliability in vivo.

Abstract (italian)

Parte I. Distrofia Facio-scapolo-omerale: follow-up clinic e ruolo dell’inattivazione del cromosoma X nelle pazienti di sesso femminile
La distrofia Facio-scapolo-omerale (FSHD) e’ una distrofia muscolare autosomica dominante caratterizzata da elevata prevaleza e variabilita’ clinica. Compromette i muscoli facciali, il cingolo pelvico e, nei casi piu’ severi, gli arti inferiori. Oltre il 95% dei pazienti presenta una contrazione delle sequenze ripetute D4Z4 sul cromosoma 4q35 che determina l’ipometilazione della regione e la sovraespressione di un fattore citotossico, DUX4. In circa il 5% dei pazienti, chiamati FSHD2, l’ipometilazione del D4Z4 e’ dovuta a mutazione di SMCHD1, un gene coinvolto nell’inattivazione del cromosoma X durante l’embriogenesi. Lo scopo dello studio e’ di valutare la progressione clinica della FSHD durante un periodo di follow-up di 5 anni, usando la Clinical Severity Score (CSS), una scala precedentemente validata dal network italiano per la FSHD. Inoltre, considerando il ruolo di SMCHD1 nel controllo epigenetico del cromosoma X e le differenze nella severita’ fenotipica tra i sessi, e’ stato analizzato il pattern di inattivazione del cromosoma X per verificare se questo possa rappresentare un modificatore genetico della malatttia.
Il campione di studo era costituito da 55 pazienti FSHD (29 maschi e 26 femmine) provenienti dal Centro Neuromuscolare di Padova. Tutti i pazienti erano portatori di una frammento D4Z4 di dimensioni patologiche tra 17 e 40 kb. I pazienti valutati tramite il CSS al tempo T0 sono stati rivalutati dopo una media di 5 anni (T1). Lo score di ciascun distretto muscolare, il CSS totale e lo score MRC sono stati registrati e comparati tra T0 e T1.
L’inattivazione del cromosoma X e’ stata analizzata in 38 FSHD1 e FSHD2 pazienti femmine misurando il grado di metilazione delle sequenze ripetute CAG del recettore degli androgeni. Il DNA genomico e’ stato digerito con enzimi di restrizione metilazione sensibili (HpAII and HhAI), amplificato tramite PCR e infine genotipizzato. 48 soggetti sani sono stati studiati come controlli e il pattern di inattivazione del cromosoma X e’ stato correlato con il grado di coinvolgimento muscolare misurato con il CSS.
Dopo 6 anni di follow-up, la differenza media del CSS tra T0 e T1, lo score MRC del bicipite, tricipite e tibiale anteriore sono risultati significativi solo nel gruppo dei probandi. Nessuna differenza significativa e’ emersa per periodi di follow-up inferiori e nel gruppo dei familiari. La progressione di malattia e’ risultata indipendente dalla dimensione del frammento D4Z4 e non sono risultate differenze tra i sessi. Il pattern di inattivazione del cromosoma X e’ risultato normalmente distribuito sia nei pazienti sia nei controlli. Una moderata correlazione lineare e’ stata riscontrata tra la percentuale di inattivazione del cromosoma X e la severita’ del cingolo scapolare ma non negli altri distretti muscolari.
In conclusion, i sintomi della FSHD appaiono progredire lentamente nel tempo e, sebbene il CSS rappresenti un valido strumenti per la caratterizzazione dei pazienti, manca di sensitivita’ nell’identificazione di sfumate modificazioni cliniche perfino in un periodo di 5 anni. Pertanto il suo uso nel follow-up appere limitato. Inoltre, il pattern di inattivazione del cromosoma X riflette la distribuzione normale osservata nelle femmine sane e correla solo modestamente con la severita’ della malattia. Questi ultimi risultati suggeriscomo che diversi regolatori genetici sono coinvolti nella completa espressione fenotipica della malattia rendendo complessa la valutazione di potenziali terapie.

Parte II. SHP2: un nuovo target terapeutico nella miastenia-MuSK.
La miastenia grave mediata da anticorpi anti Muscle Specific Kinase (MuSK-MG) e’ una malattia autoimmune che compromette la trasmissione neuromuscolare determinando faticabilita’ e una debolezza muscolare generalizzata. In condizioni fisiologiche, l’agrin attiva il complesso LRP4-MuSK, iniziando una cascata fosforilativa che culmina con la clusterizzazione dei recettori dell’acetilcolina (AChR). SH2 domani-containing phosphatase (SHP2) e’ un regolatore negativo della clusterizzazione degli AchRs che inibisce la fosforilazione di MuSK. Nella MuSK-MG, autoanticorpi contro MuSK, appartenenti soprattutto alla sottoclasse delle IgG4, bloccano l’interazione tra MuSK e LRP4 e, pertanto, la sua attivazione. La ridotta popolazione di IgG1-3 sembra operare in modo differente. Sebbene la MuSK-MG sia una malattia trattabile, una terapia mirata specificamente ai meccanismi patogenetici sottostanti non e’ ancora disponibile. Lo scopo dello studio e’ di confermare ed estendere i risultati preliminari che hanno dimostrato l’effetto in vitro di uno specifico inibitore di SHP2, NSC-87877, come potenziale specifico trattamento per la MuSK-MG.
Le IgG totale e le relative sottoclassi (IgG1-3, IgG4) sono state purificate dal plasma di 3 pazienti MuSK-MG. Il titolo degli anticorpi anti-MuSK e’ stato misurato tramite test radioimmunologico. Per testare gli effetti di NSC-87877 sulla fosforilazione di MuSK e sulla clusterizzazione degli AchR, sono stati usati miotubi di cellule C2C12. I miotubi sono stati incubati con concentrazioni crescenti di NSC-87877 a differenti intervalli di tempo (da 15 a 360 minuti) usando rispettivamente agrin e DMEM come controlli positivo e negativo. Per verificare che il farmaco fosse in grado di contrastare gli effetti patogenici degli anticorpi anti-MuSK, i miotubi sono stati esposti ad agrin assieme alle IgG totali, IgG1-3 e IgG4 anti-MuSK e in presenza o assenza di NSC-87877. La fosforilazione tirosinica e l’espressione di MuSK sono state misurate tramite western blotting e il livello di fosforilazione espresso come ratio dei valori densitometrici tra la MuSK fosforilato e MuSK totale. Per la quantificazione della clusterizzazione degli AChRs, i miotubi sono stati colorati con α-bungataroxin-594 e le immagini acquisite e analizzate tramite il software ImageJ. Per ogni esperimento sono state acquisite almento 20 immagini con successiva conta dei cluster di dimensioni superiori > 5 μm.
In assenza di agrin, NSC-87877 ha determinato un aumento dose-dipendente sia della fosforilazione di MuSK sia del numero dei cluster di AChRs, con effetto massimo alla dose di 100 μM e dopo 40 minuti di incubazione. Alla dose di 100 μM, NSC-87877 ha inoltre incrementato la fosforilazione di MuSK in presenza delle IgG totali e dell IgG4 purificate mentre nessun cambiamento significativo e’ stato osservato con le IgG1-3. Ciononostante, sia le IgG totali sia tutte le sottoclassi IgG hanno determinato la dispersione dei clusters di AChRs (vedi anche Koneczny et al, 2013) e NSC-87877 e’ risultato in grado di revertire i loro effetti patologici in tutti i campioni studiati.
L’inibizione di SHP2 da parte di NSC-87877 e’ in grado di indurre la fosforilazione di MuSK e di aumentare la clusterizzazione degli AChRs indipendentemente dalla stimolazione diretta da parte di agrin. Inoltre, NSC-87877 induce l’attivazione di MuSK nonostante gli effetti inibitori degli anticorpi IgG4 anti-MuSK e aumenta la clusterizzazione degli AChRs in presenza di tutte le differenti sottoclassi di anticorpi. Pertanto, indipendentemente dal tipo di sottoclassi IgG, l’inibisione di SHP2 rappresenta una potenziale strategia terapeutica nella miastenia anti-MuSK e ulteriori studi potranno dimostrare la sua efficacia e affidabilita’ in vivo.

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EPrint type:Ph.D. thesis
Tutor:Pegoraro, Elena
Supervisor:Vincent, Angela
Ph.D. course:Ciclo 30 > Corsi 30 > MEDICINA SPECIALISTICA "G.B. MORGAGNI"
Data di deposito della tesi:22 January 2018
Anno di Pubblicazione:22 January 2018
Key Words:FSHD, chromosome X inactivation, SMCHD1, miasthenia gravis, MuSK, SHP2
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/26 Neurologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:11055
Depositato il:30 Oct 2018 11:05
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