Publication
Molecular characterization of the Portuguese patients with defects in GlcNAc-phosphotransferase: a key enzyme in the M6-P dependent lysosomal trafficking
| dc.contributor.author | Coutinho, Maria Francisca | |
| dc.contributor.author | Encarnação, Marisa | |
| dc.contributor.author | Gomes, Rui | |
| dc.contributor.author | Prata, Maria João | |
| dc.contributor.author | Lacerda, Lúcia | |
| dc.contributor.author | Bargal, Ruth | |
| dc.contributor.author | Filocammo, Mirella | |
| dc.contributor.author | Raas-Rothschild | |
| dc.contributor.author | Tappino, Barbara | |
| dc.contributor.author | Laprise, Cathrine | |
| dc.contributor.author | Sirois-Gagnon, D. | |
| dc.contributor.author | Costa, Roberto | |
| dc.contributor.author | Ribeiro, Helena | |
| dc.contributor.author | Lopes, Lurdes | |
| dc.contributor.author | Alves, Sandra | |
| dc.date.accessioned | 2012-03-16T16:06:30Z | |
| dc.date.available | 2012-03-16T16:06:30Z | |
| dc.date.issued | 2009-02-07 | |
| dc.description.abstract | Introduction: GlcNAc-phosphotransferase is one of the enzymes responsible for the formation of M6P residues and plays a key role in lysosomal trafficking, since most soluble acid hydrolases reach these organelles through the M6P pathway. It is composed of six subunits (α2β2γ2), products of two genes recently cloned: GNPTAB (mutated in mucolipidosis II/IIIA patients) and GNPTG (mutated in MLIIIC patients). Methods: Using both gDNA and cDNA extracted from patient’s fibroblasts, we performed a molecular study of both genes in 13 MLII/III patients (10Portuguese, 1Finnish, 1Spanish of Arab origin and 1Indian). Expression studies were performed by quantitative real-time PCR. Results: We identified 11 different mutations, 8 of them novel: 6 in the GNPTAB gene (c.121delG;c.440delC;c.2249_50insA;W81L;I403T and E667) and 2 in the GNPTG gene (c.610-1G.T and c.639delT). Interestingly, although the MLII-causing mutations have been mostly found to be private or rare, there is one (c.3503_3504delTC) that shows a broad distribution having been detected among different populations. This same mutation was also the most frequent one in our patients. Such distribution pattern prompted us to perform a haplotypic study. We analysed 37 patients (23Italians, 8Arab Muslims, 1Turkish and 5Portuguese) for 3 intragenic polymorphisms and 2 microsatellite markers flanking the GNPTAB gene, identifying a common haplotype. Regarding the mRNA expression studies, real-time results suggest the existence of feedback regulation mechanisms between α/β and the γ subunits. Discussion/Conclusion: This work enabled the establishment of a strong genotype-phenotype correlation, which is of crucial importance to an improved genetic counselling for ML families. The sharing of an ancestral haplotype by patients carrying the deletion implies a common origin of this mutation, while the higher level of diversity observed at the most distant locus indicates that it is a relatively ancient one. The developed strategies constitute valuable tools that allow carrier detection and prenatal- molecular diagnostics of these diseases. | por |
| dc.identifier.uri | http://hdl.handle.net/10400.18/836 | |
| dc.language.iso | eng | por |
| dc.publisher | Instituto Nacional de Saúde Doutor Ricardo Jorge, IP | por |
| dc.subject | Doenças Genéticas | por |
| dc.title | Molecular characterization of the Portuguese patients with defects in GlcNAc-phosphotransferase: a key enzyme in the M6-P dependent lysosomal trafficking | por |
| dc.type | conference object | |
| dspace.entity.type | Publication | |
| oaire.citation.conferencePlace | Porto, Portugal | por |
| oaire.citation.title | 13ª Reunião da Sociedade Portuguesa de Genética Humana, 19-21 Novembro 2009 | por |
| rcaap.rights | restrictedAccess | por |
| rcaap.type | conferenceObject | por |