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Nascimbeni, Anna Chiara (2009) Glycogenosys type II and Danon Disease: molecular study and muscle pathology. [Tesi di dottorato]

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Abstract (inglese)

The objective of this study was to examine at molecular, biochemical and muscle pathology level two groups of patients affected with Danon disease and GSDII, in order to get new insights that might help in tracing genotype-phenotype correlations and to delineate their pathological mechanisms.
Glycogen storage disease type II (GSDII) is an autosomal recessive disorder (OMIM # 232300) caused by the deficiency of the lysosomal enzyme acid ?-glucosidase or acid maltase (EC 3.2.1.20/3), which catalyses the hydrolysis of ?-1,4 and ?-1,6 links of glycogen. The enzyme deficiency leads to lysosomal accumulation of glycogen that results in different clinical phenotypes, ranging from the : the severe infantile-onset form to the childhood, juvenile or adult-onset forms (late-onset forms).
We investigated 23 patients with infantile-onset or late-onset glycogen storage disease type II by enzyme activity, protein expression by immunoblotting, GAA gene mutations, and muscle pathology including immunolabeling for Golgi and sarcolemmal proteins.
The enzyme activity resulted absent or minimal in infantile-onset cases and variably reduced in late-onset patients. Genotype-phenotype correlation (seven novel mutations were found) showed that most late-onset patients had the heterozygous c.–32-13T>G leaky splicing mutation (one patient was homozygous), but the course of the disease was often difficult to predict on the basis of the mutations alone. One important and novel result from our study came from the Western blot analysis of the different maturative forms of acid ? –glucosidase protein in the muscle from patients with GSDII. We have demonstrated that the muscle from patients with GSDII has a predominant expression of inactive forms of acid ?-glucosidase protein and severely reduced or absent levels of the mature forms. Furthermore, the residual amount of the mature forms of the protein on blotting correlated with the level of enzyme activity in muscle.
We first report a different molecular weight of the mature and the intermediate forms of the protein between patients and controls that we attribute to an excessive sialylation of mutant proteins. This is likely caused by a delayed transport and longer transit of the inactive proteins in the Golgi where the sialyltransferases are localized. Supporting this hypothesis, we observed that, in both infantile and late-onset patients, there is an enhanced proliferation of the Golgi apparatus. On the other hand, we did not find any increased expression of LAMP-1 in patients with GSDII, possibly due to the fact that only a minor proportion of mutant enzyme protein is able to reach the lysosomes. Another interesting data rises from the morphologic analysis of the different cellular organelles. Interestingly, we observed a differential degree of dysfunction of endocytic and autophagic pathways in patients with infantile and late-onset GSDII. In late-onset acid maltase deficient muscle, vacuolar membranes expressed sarcolemmal proteins, such as caveolin-3 and dystrophin (previously classified as type 2 vacuoles) and not in the infantile form of the disease (type 4 vacuoles, lakes of glycogen). These features are possibly due to reduced membrane proliferation and vesicular movement in the overcrowded muscle fibers of Pompe disease, and to the membrane remodelling occurring only in patients with late-onset GSDII, which would be a protective mechanism to prevent membrane rupture during fiber contraction.
This observation is important because the pathogenesis of the autophagosomes has not yet been fully investigated. Autophagy and membrane remodelling, which is peculiar to late onset disease, might modify a clear response to enzyme replacement therapy and, also, compartmentalize the delivery of the recombinant enzyme.
Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues, including leukocytes, explaining the multisystem clinical involvement. Skeletal muscle immunopathology showed that mutant protein was not localized in the Golgi complex, vacuolar membranes expressed sarcolemmal- specific proteins, and the degree of muscle fiber vacuolization correlated with clinical muscle involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification. The random X-chromosome inactivation found in muscle and leukocytes excluded the possibility that selective involvement of some tissues in females is due to skewed X-chromosome inactivation. Therefore, biochemical analysis of leukocytes might be used for screening in male patients, but genetic screening is required in females.

Abstract (italiano)

Scopo di questo studio è stato quello di analizzare a livello molecolare, biochimico e della patologia muscolare due gruppi di pazienti affetti dalla malattia di Danon e da glicogenosi di tipo II, in modo da acquisire nuove informazioni utili a tracciare possibili correlazioni genotipo-fenotipo e a chiarire i meccanismi patologici alla base di queste patologie.
La Glicogenosi di tipo II (GSDII) è una malattia autosomica recessiva (OMIM # 232300) causata da un deficit dell’enzima mitocondriale ?-glucosidasi o maltasi acida (EC 3.2.1.20/3), che catalizza l’idrolisi dei legami glicogeno ? -1,4 e ? -1,6. Tale deficit enzimatico porta all’accumulo a livello lisosomale di glicogeno, che genera un’ampia eterogeneità clinica, che spazia da casi con esordio infantile e quadro clinico molto severo a forme più benigne con esordio tardivo nell’età adulta. Sono stati analizzati 23 pazienti con deficit di ?-glucosidasi acida per l’attività enzimatica mediante saggio fluorimetrico, l’espressione proteica mediante immunoblotting, la presenza di mutazioni nel gene GAA con SSCP e la patologia muscolare mediante immunocolorazione del Golgi e delle proteine sarcolemmali.
L’attività enzimatica è risultata assente o minima nei casi ad esordio infantile e variabilmente ridotta nei pazienti con esordio tardivo. Le correlazioni genotipo-fenotipo indicano che la maggior parte dei pazienti ad esordio tardivo presentano la mutazione “leaky splicing” c.–32-13T>G in eterozigosi (un paziente era omozigote), ma il decorso della malattia è spesso difficile da prevedere solo sulla base delle mutazioni.
Un risultato interessante deriva dall’analisi mediante western blot dell’espressione dell’?-glucosidasi nei pazienti: abbiamo infatti dimostrato che il muscolo di questi pazienti esprime prevalentemente forme inattive/immature dell’enzima ?-glucosidasi, mentre la forma matura della proteina è assente o presente a livelli molto ridotti. Inoltre, si è visto che l’eventuale quantità residua di forme proteiche mature riscontrate al western blot correla con i livelli di attività enzimatica riscontrati nel muscolo di questi pazienti. Il peso molecolare sia delle forme mature che di quelle immature/inattive è risultato essere maggiore nei pazienti rispetto ai muscoli di controllo. Attribuiamo tali differenze ad un’eccessiva sialilizzazione delle forme proteiche non funzionali, causata probabilmente da un loro trasporto ritardato o da una loro ritenzione nel complesso di Golgi, in cui agiscono le sialil-transferasi. A sostegno di tale ipotesi, abbiamo riscontrato una proliferazione del Golgi nelle fibre muscolari dei pazienti, causata possibilmente dalla ritenzione delle forme enzimatiche inattive, che non possono venire correttamente veicolate ai lisosomi. Le membrane vacuolari esprimono le proteine sarcolemmali nei pazienti con esordio tardivo ma non in quelli ad esordio infantile, suggerendo un’autofagia estesa ed un rimodellamento della membrana vacuolare nei pazienti ad esordio tardivo.
La Malattia di Danon ha ereditarietà di tipo dominante legato al cromosoma X ed è causata da mutazioni nel gene LAMP2 (Lysosomal Associated Membrane Protein-2), e si presenta con cardiomiopatia ipertrofica, miopatia e ritardo mentale.
Per studiare gli effetti delle mutazioni nel gene LAMP2 sull’espressione proteica in diversi tessuti, abbiamo effettuato uno screening molecolare ed un’analisi del difetto proteico sul tessuto muscolare, cardiaco, sui leucociti e fibroblasti di 9 soggetti maschi non correlati tra loro, con cardiomiopatia ipertrofica e miopatia vacuolare.
Tre dei 9 soggetti analizzati hanno evidenziato un deficit proteico di LAMP2 generalizzato. Tale difetto è stato infatti riscontrato in tutti i tessuti da noi analizzati: tessuto muscolare scheletrico e cardiaco, leucociti e fibroblasti. Questo risultato indica che l’analisi biochimica può essere svolta in modo non invasivo sui leucociti, e potrebbe quindi essere impiegata nello screening dei soggetti maschi; inoltre, questo deficit multi-organo di proteina LAMP2 potrebbe spiegare il coinvolgimento clinico multisistemico.
Abbiamo inoltre esteso l’analisi anche alla madre di un affetto: in questo caso il muscolo, i fibroblasti e i leucociti presentano livelli proteici comparabili al controllo normale.
Sono state identificate mutazioni nel gene LAMP2 in tutti e 3 i pazienti maschi e nella femmina eterozigote. Ciascun paziente presentava una mutazione diversa e non riportata precedentemente in letteratura: sono tutte mutazioni nulle (nonsenso o frame-shifting) che ci si aspetta diano origine ad una proteina tronca, con perdita del dominio trans-membrana.
’istopatologia muscolare ha evidenziato una vacuolizzazione fibrale estesa e della degenerazione . L’analisi immunopatologica del muscolo scheletrico ha evidenziato che non vi è proliferazione del complesso del Golgi nei pazienti, che le membrane vacuolari esprimono le proteine sarcolemmali e che il grado di vacuolizzazione correla con il coinvolgimento clinico a livello muscolare.
L’analisi dell’inattivazione del cromosoma X effettuata sul tessuto muscolare e sui leucociti ha escluso la possibilità che il coinvolgimento selettivo di alcuni tessuti nelle femmine sia dovuto ad una inattivazione non casuale dell’X

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Tipo di EPrint:Tesi di dottorato
Relatore:angelini , corrado
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:30 Gennaio 2009
Anno di Pubblicazione:31 Gennaio 2009
Parole chiave (italiano / inglese):Glycogen storage disease type II, Danon disease
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/26 Neurologia
Struttura di riferimento:Dipartimenti > Dipartimento di Neuroscienze
Codice ID:1733
Depositato il:30 Gen 2009
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