Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/2159
Título: Molecular and biochemical studies in genes determining missorting of lysosomal proteins
Autor: Coutinho, Maria Francisca
Palavras-chave: Doenças Genéticas
Lysosomal Targeting
Mucolipidosis Type II (ML II)
Mucolipidosis Type III (ML III)
Data: 4-Set-2013
Resumo: To fulfill their degradative function lysosomes must receive specific proteins, which after being synthesized in the endoplasmic reticulum (ER) need then to be directed to the trans Golgi network (TGN) for further processing and lysosomal targeting. The major pathway for lysosomal enzyme delivery, the M6P-dependent pathway, requires the recognition of a specific mannose-6-phosphate signal selectively added to lysosomal enzymes in the TGN. Nevertheless, increasing evidence indicates the existence of additional or alternative pathways, M6P-independent, from the TGN to lysosomes. Presently, two alternative receptors which mediate that transport have been described: the lysosomal integral membrane protein LIMP-2 and sortilin. Impairments in the M6P pathway are responsible for two well-defined lysosomal storage disorders: Mucolipidosis types II (MLII) and III (MLIII), which are caused by total or partial loss of GlcNAc-1-phosphotransferase activity, respectively. This enzyme is responsible for the first of two catalytic steps that ultimately result in the formation of the M6P recognition marker, and is encoded by two independent genes: GNPTAB and GNPTG. In total, a set of 23 unrelated ML II and III cases from several origins was screened, leading to the identification of 18 different mutations: 16 in the GNPTAB gene and 2 in the GNPTG gene. Of those, 13 were novel: 11 in the GNPTAB gene and 2 in the GNPTG gene. All mutations identified were further analyzed with the most suitable approaches, paying special attention to the novel alterations and their effect at different levels, from molecules to the organism as a whole: mRNA and protein expression, protein subcellular location and phenotypic effects were all taken into account. Concerning the contribution of defects in the genes that code for proteins involved in the M6P-independent trafficking pathways, in a set of 120 individuals with clinical suspicion of LSD but without definitive biochemical and/or molecular diagnosis, no novel mutations were detected either on the gene that codes for LIMP-2 (SCARB2) or on the one that codes for sortilin (SORT1). So far, no evidence came that SORT1 deficiencies may be associated to LSD phenotypes. Still, enlarged sample sizes are needed in order to draw more reliable conclusions on the topic. The role of variations in SCARB2 on the broad phenotype spectrum observed for Gaucher disease (GD) patients was also addressed. After the majority of Portuguese GD patients (91 individuals) was screened, one novel SCARB2 variant was identified, reinforcing previous evidence that mutations in the gene that codes for the beta-glucocereborosidase transporter can act as GD modifiers. In general, this study reinforces the biological importance of a proper targeting of lysosomal proteins to their final destination, by highlighting the severe consequences of impairments in proteins involved in that process.
URI: http://hdl.handle.net/10400.18/2159
Aparece nas colecções:DGH - Materiais de difusão da cultura científica e de formação

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