Thesis etd-09012022-191748 |
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Thesis type
Tesi di laurea magistrale
Author
OREFICE, MARTINA
URN
etd-09012022-191748
Thesis title
Analisi funzionale in zebrafish del gene Polypyrimidine Tract-Binding Protein 1, associato a osteocondrodisplasia nell'uomo
Department
BIOLOGIA
Course of study
BIOLOGIA MOLECOLARE E CELLULARE
Supervisors
relatore Prof.ssa Ori, Michela
correlatore Prof. Scarpato, Roberto
correlatore Prof.ssa Ferraro, Elisabetta
correlatore Prof. Scarpato, Roberto
correlatore Prof.ssa Ferraro, Elisabetta
Keywords
- alcian blue
- Danio rerio
- development
- PTBP1
- shuttling
- skeletal development
- skeletal dysplasia
- zebrafish
Graduation session start date
19/09/2022
Availability
Withheld
Release date
19/09/2062
Summary
La Polypyrimidine Tract Binding Protein 1 (PTBP1) è una proteina legante l’RNA, coinvolta nella regolazione dello splicing alternativo e degli eventi citoplasmatici di traduzione e degradazione dei trascritti cellulari. Due varianti de novo di PTBP1, localizzate a livello delle sequenze codificanti per i segnali di shuttling di PTBP1, sono state identificate in una corte di 23 pazienti, che presentano displasia scheletrica (SD) e disabilità intellettiva (ID) moderata. Dati preliminari su fibroblasti umani evidenziano una ritenzione citoplasmatica delle varianti identificate. Le analisi di sovraespressione di PTBP1 umano in zebrafish suggeriscono che la proteina wild-type sia coinvolta in meccanismi di sviluppo scheletrico. Inoltre, è stato verificato che le alterazioni dello shuttling causate dalle due varianti de novo, determinano un diverso impatto fenotipico della sovraespressione di tali forme rispetto alla forma wild-type. L’analisi dell’espressione genica di sox9a, master regulator dello sviluppo condrogenico, suggeriscono che il guadagno di funzione di PTBP1 nello sviluppo scheletrico possa svolgersi a valle di sox9a.
The Polypyrimidine Tract-Binding Protein 1 is an RNA binding protein, involved in regulation of alternative splicing and most steps of mRNA metabolism. Two likely-pathogenic PTBP1 variants have been identified in a cohort of 23 individuals, with congruent clinical features of skeletal dysplasia with variable developmental delay. Preliminary data on human fibroblasts show cytoplasmic retention of the identified variants. Overexpression analyses of human PTBP1 in zebrafish suggest that the wild-type protein is involved in skeletal development mechanisms. In addition, it has been verified that the altered shuttling of mutated PTBP1 associates with a different phenotypic impact of the overexpression of these forms compared to the wild-type form. Analysis of sox9a gene expression, a master regulator of chondrogenic development, suggests that gain of function of PTBP1 might act downstream of sox9a. Further analysis would deepen the role of PTBP1, enlightened in this thesis, in skeletal development.
The Polypyrimidine Tract-Binding Protein 1 is an RNA binding protein, involved in regulation of alternative splicing and most steps of mRNA metabolism. Two likely-pathogenic PTBP1 variants have been identified in a cohort of 23 individuals, with congruent clinical features of skeletal dysplasia with variable developmental delay. Preliminary data on human fibroblasts show cytoplasmic retention of the identified variants. Overexpression analyses of human PTBP1 in zebrafish suggest that the wild-type protein is involved in skeletal development mechanisms. In addition, it has been verified that the altered shuttling of mutated PTBP1 associates with a different phenotypic impact of the overexpression of these forms compared to the wild-type form. Analysis of sox9a gene expression, a master regulator of chondrogenic development, suggests that gain of function of PTBP1 might act downstream of sox9a. Further analysis would deepen the role of PTBP1, enlightened in this thesis, in skeletal development.
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