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Benetti, Elisa (2013) Le podocitopatie: analisi di varianti genetiche in forme familiari e sporadiche. [Tesi di dottorato]

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Abstract (inglese)

Background and aims. The understanding of proteinuric glomerular diseases has greatly expanded in recent years, thanks to the advances in the filed of molecular biology. An increased number of podocyte-expressed genes have been identified, placing glomerular epithelial cell (podocyte) at the centre of the disease mechanisms of podocitopathies. Podocitopathies include a variety of causes and histopathologic findings, despite similar clinical presentation. Even though the development of the glomerulopathy that leads to proteinuria may not only be explained by a genetic alteration, the identification of a genetic disease may be essential to define a patient-tailored therapy (aimed to avoid unnecessary and potentially detrimental drugs, as immunosuppressants) and long-term prognosis (progression to end stage renal disease, risk of post-transplantation recurrence and necessity of specific therapy, possibility of living-related transplantation).
Patients and methods. Genetic testing by direct sequencing of the genes more frequently associated with podocitopathies (NPHS2, WT1, PLCE1, NPHS1) and Next Generation Sequencing (including 46 genes) were carried out in 40 children affected by familial or sporadic podocitopathy. Clinical and histopathological features, as well as outcomes, were also retrospectively and prospectively analysed.
Results. A genomic alteration was found in 20/40 patients (50%): 6/40 children (15%) had a variation in NPHS2 gene (associated with focal segmental glomerulosclerosis - FSGS); in 4/6 cases, the detected sequence variant was novel. 11 patients (27.5%) carried a mutation in WT1 gene (associated with FSGS in 6 and with diffuse mesangial sclerosis – DMS - in 5 children); in 4/11 cases, the detected variation was novel. 3 children had novel sequence variations in PLCE1 gene (the histological picture was FSGS in 2 and DMS in 1). The detected alterations were found to be pathogenetic in 18/20 patients. Genetic analysis was extended to parents in 12/20 cases.
Conclusions. The high frequency of mutation in our series of children affected by podocitopathies confirms the importance of genetic alterations in the pathogenesis of these diseases. Therefore, a correct diagnostic pathway cannot exclude a genetic screening, at least for genes more frequently associated with proteinuria and nephrotic syndrome (namely, NPHS2, WT1 e PLCE1). In clinical practice, the ethiological diagnosis is essential to an accurate work up of the patient (with direct outcomes on therapeutic strategies and prognosis) and may contribute to the optimization of health resources.

Abstract (italiano)

Background e scopo. I recenti avanzamenti delle metodologie nel campo della biologia molecolare hanno condotto all’identificazione di un numero crescente di geni associati alle glomerulopatie proteinuriche, ponendo al centro dell’attenzione il podocita e aprendo nuove prospettive nella conoscenza dei meccanismi patogenetici delle podocitopatie. Le podocitopatie rappresentano una condizione complessa, caratterizzata da un’ampia eterogeneità, pur essendo le manifestazioni cliniche relativamente omogenee. Sebbene lo sviluppo della glomerulopatia che determina la proteinuria non sia unicamente spiegato dalla presenza di un’anomalia genetica, una diagnosi di malattia genetica può risultare l’elemento di svolta nella definizione di un percorso terapeutico mirato (evitando farmaci inutili e potenzialmente dannose, come gli immunosoppressori) e di una prognosi anche a lungo termine (rischio di progressione ad insufficienza renale, probabilità di recidiva sul trapianto, necessità di terapie mirate post-trapianto, opportunità di eseguire un trapianto da donatore vivente).
Pazienti e metodi. In 40 bambini con podocitopatia sporadica o familiare, abbiamo eseguito un’analisi delle varianti genetiche sia tramite sequenziamento diretto dei geni più frequentemente associati alle podocitopatie (NPHS2, WT1, PLCE1, NPHS1) sia mediante Next Generation Sequencing, utilizzando una piattaforma comprendente 45 geni. Inoltre, sono state analizzate retrospettivamente e in senso prospettico le caratteristiche cliniche, il quadro istopatologico e l’outcome.
Risultati. Un’alterazione genomica è stata riscontrata in 20/40 pazienti (50%): 6/40 bambini (15%) presentavano un’alterazione del gene NPHS2 (associata in tutti i casi a quadro istologico di glomerulosclerosi focale e segmentale - FSGS); in 4/6 casi, la variazione di sequenza riscontrata era nuova. 11 pazienti (27.5%) presentavano una mutazione di WT1 (con istologia di FSGS in 6 e di sclerosi mesangiale diffusa – DMS - in 5); in 4/11 casi, la variazione di sequenza era nuova. 3 bambini presentavano delle nuove variazioni di sequenza del gene PLCE1 (con quadro istologico di FSGS in 2 e DMS in 1). Le alterazioni riscontrate si sono rivelate patogenetiche in 18/20 pazienti. L’analisi genetica è stata estesa ai genitori in 12/20 casi.
Conclusioni. L’elevata frequenza di mutazioni nella nostra casistica di bambini affetti da podocitopatia conferma la rilevanza dei difetti genetici nella patogenesi della podocitopatie, per cui un corretto iter diagnostico non può non prevedere uno screening genetico, almeno per i geni più frequentemente associati a proteinuria e sindrome nefrosica (in particolare, NPHS2, WT1 e PLCE1). Nella pratica clinica, la definizione eziologica della diagnosi permette un accurato work up del paziente (con ricadute dirette sulle scelte terapeutiche e la formulazione prognostica) e, di conseguenza, l’ottimizzazione delle risorse sanitarie.

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Tipo di EPrint:Tesi di dottorato
Relatore:Perilongo, Giorgio
Correlatore:Murer, Luisa
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > MALATTIE RARE, GENETICA, BIOLOGIA E BIOCHIMICA
Data di deposito della tesi:21 Dicembre 2013
Anno di Pubblicazione:21 Dicembre 2013
Parole chiave (italiano / inglese):Next Generation Sequencing Podocitopatie/Podocitopathies
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:6221
Depositato il:10 Nov 2014 16:43
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