Monticelli, Maria (2022) The role of missense mutations in diseases: two sides of a coin. [Tesi di dottorato]
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | The role of missense mutations in diseases: two sides of a coin |
| Creators: | Creators Email Monticelli, Maria maria.monticelli@unina.it |
| Date: | 10 March 2022 |
| Number of Pages: | 204 |
| Institution: | Università degli Studi di Napoli Federico II |
| Department: | Biologia |
| Dottorato: | Biologia |
| Ciclo di dottorato: | 34 |
| Coordinatore del Corso di dottorato: | nome email Esposito, Sergio sergio.esposito@unina.it |
| Tutor: | nome email Cubellis, Maria Vittoria UNSPECIFIED |
| Date: | 10 March 2022 |
| Number of Pages: | 204 |
| Keywords: | Missense mutations; drug discovery; rare diseases; Beckwith-Wiedemann; PMM2-CDG; Fabry disease; COVID-19; data mining; WES; drug repurposing; 31P-NMR |
| Settori scientifico-disciplinari del MIUR: | Area 05 - Scienze biologiche > BIO/10 - Biochimica Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare Area 05 - Scienze biologiche > BIO/12 - Biochimica clinica e biologia molecolare clinica |
| Date Deposited: | 21 Mar 2022 20:01 |
| Last Modified: | 28 Feb 2024 10:46 |
| URI: | http://www.fedoa.unina.it/id/eprint/14459 |
Collection description
Missense mutations play a central role in non-physiological conditions. On the one hand, they represent the molecular basis of many genetic diseases, particularly rare diseases; on the other hand, common missense variants in the general population can influence the course of different diseases. The present Ph.D. project aimed at deepening this topic by using different approaches and techniques. Whole-exome sequencing analysis (WES) was employed to establish the genetic causes of four cases of Beckwith-Wiedemann syndrome associated with Multi-Locus Imprinting Disturbance, and in silico analysis of the identified mutations of interest was performed to figure out their role on the mutant protein, PADI6. In silico docking was used as a starting point for rational drug discovery to find pharmacological chaperones (PC) for the phosphomannomutase-2 deficiency (PMM2-CDG). In vitro expression of recombinant proteins and their analysis via canonical methods based on spectrofluorimetry or innovative techniques based on 31P-NMR, allowed the validation of in silico results. A potential PC for PMM2-CDG was identified this way, namely β-glucose-1,6-bisphosphate. Cell-based techniques represented the chosen method for drug repurposing. In particular, the possibility of potentiating approved pharmacological chaperones by modulation of proteostasis was evaluated for Fabry-Anderson disease. Aspirin turned out to enhance and prolong the PC-induced protein stabilization. COVID-19 outbreak represented the starting point to investigate the role of common missense variants in influencing various conditions. Bioinformatics analysis of literature was employed to identify common variants in the general population potentially associated with SARS-CoV*. WES analysis on patients with different clinical outcomes confirmed the prediction. In particular, one variant was identified in TMPRSS2 that showed a deleterious effect on the protease and a protective effect on the patients, especially in some age- and sex-related sub-groups.
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