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Zanetti, Alessandra (2008) Caratterizzazione molecolare delle variazioni di sequenza del gene hIDS in pazienti affetti da sindrome di Hunter. [Ph.D. thesis]

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Abstract (english)

Hunter syndrome or mucopolysaccharidosis type II (MPS II) is an X-linked disorder caused by the deficienct activity of the lysosomal enzyme iduronate-2-sulfatase (IDS) causing accumulation of partially degraded dermatan and heparan sulfates in various tissues and progressive impairment of function.
Hunter syndrome is a disease with multiorgan and multisystem involvement that shows a complete spectrum of phenotypes from attenuated to intermediate and severe.
The diagnosis is based on the collection of clinical data, on dosage of urine GAG levels and on mutational analysis of the hIDS gene.
Until recently, the management of Hunter syndrome has been palliative and focused on the treatment of signs and symptoms. Enzyme replacement therapy (ERT) with recombinant human iduronate-2- sulfatase (idursulfase) has lately been introduced. ERT has been shown to improve many of the sign and symptoms and overall wellbeing of patients with MPS II.
The IDS locus, located on Xq27.3-q28, spans a region of 24 kb and contains 9 exons. At 20 kb telomeric and in opposite orientation to the IDS gene, a pseudogene, IDS2, containing sequences homologous to exons 2, 3 and introns 2, 3, 7 is present. To date, more than 330 different mutations have been identified in the IDS gene: 89% being small variations, while 11% major structural alterations. The most common rearrangement is an intrachromosomal homologous recombination event between IDS and IDS-2 sequences.
Fifteen unrelated patients were analyzed in this study, 11 Italian and 4 Brazilian. Among the 15 cases analyzed 16 sequence variations were detected: 12 point mutations or small deletions, one medium size deletion, 2 large deletions, a recombination associated to a deletion. Among them 9 were novel sequence variations and 2 were de novo mutations as the mother didn’t result carrier.
The rarity of the disease and the fact that most mutations are private make evalutation of the genotype-phenotype correlation very difficult.
Among the 15 patients described, 9 showed a severe form of the pathology, 4 an intermediate one and 2 were mild. A genotype-fenotype relationship was attempted for each case. The complete absence of functional enzyme caused by total or partial gene deletion or by gene-pseudogene rearrangement seemed to result in a severe form in the cases analyzed. Genotype-phenotype correlation for point mutations was more complex and a specific discussion was necessary for each sequence variation.
Molecular analysis is a valid method to support clinical and biochemical diagnosis confirming the results obtained from the previous approaches. Gene analysis is the only secure method to identify female carriers among a patient’s relatives and therefore it is essential in genetic counselling. Furthermore, it is useful in prenatal diagnosis in order to detect the mutation carried by a heterozygote mother.


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EPrint type:Ph.D. thesis
Tutor:Scarpa, Maurizio
Supervisor:Tomanin, Rosella
Ph.D. course:Ciclo 20 > Scuole per il 20simo ciclo > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > GENETICA BIOCHIMICA E MOLECOLARE
Data di deposito della tesi:30 June 2008
Anno di Pubblicazione:30 June 2008
Key Words:gene hIDS, pseudogene IDS-2, mutazioni, ricombinazione, sindrome di Hunter, mucopolisaccaridosi tipo II
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/03 Genetica medica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Pediatria
Codice ID:1071
Depositato il:02 Dec 2008
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