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Coutinho M.F.,INSA | Lacerda L.,Biochemical Genetics Unit | Pinto E.,Biochemical Genetics Unit | Ribeiro H.,Biochemical Genetics Unit | And 4 more authors.
Clinical Genetics | Year: 2015

The newly-synthesized lysosomal enzymes travel to the trans-Golgi network (TGN) and are then driven to the acidic organelle. While the best-known pathway for TGN-to-endosome transport is the delivery of soluble hydrolases by the M6P receptors (MPRs), additional pathways do exist, as showed by the identification of two alternative receptors: LIMP-2, implicated in the delivery of β-glucocerebrosidase; and sortilin, involved in the transport of the sphingolipid activator proteins prosaposin and GM2AP, acid sphingomyelinase and cathepsins D and H. Disruption of the intracellular transport and delivery pathways to the lysosomes may result in lysosomal dysfunction, predictably leading to a range of clinical manifestations of lysosomal storage diseases. However, for a great percentage of patients presenting such manifestations, no condition is successfully diagnosed. To analyse if, in this group, phenotypes could be determined by impairments in the known M6P-independent receptors, we screened the genes that encode for LIMP-2 and sortilin. No pathogenic mutations were identified. Other approaches will be needed to clarify whether sortilin dysfunction may cause disease. © 2014 John Wiley & Sons A/S.

Coutinho M.F.,Research and Development Unit | Lacerda L.,Biochemical Genetics Unit | Alves S.,Research and Development Unit
Biochemistry Research International | Year: 2012

Impaired degradation of glycosaminoglycans (GAGs) with consequent intralysosomal accumulation of undegraded products causes a group of lysosomal storage disorders known as mucopolysaccharidoses (MPSs). Characteristically, MPSs are recognized by increased excretion in urine of partially degraded GAGs which ultimately result in progressive cell, tissue, and organ dysfunction. There are eleven different enzymes involved in the stepwise degradation of GAGs. Deficiencies in each of those enzymes result in seven different MPSs, all sharing a series of clinical features, though in variable degrees. Usually MPS are characterized by a chronic and progressive course, with different degrees of severity. Typical symptoms include organomegaly, dysostosis multiplex, and coarse facies. Central nervous system, hearing, vision, and cardiovascular function may also be affected. Here, we provide an overview of the molecular basis, enzymatic defects, clinical manifestations, and diagnosis of each MPS, focusing also on the available animal models and describing potential perspectives of therapy for each one. Copyright © 2012 Maria Francisca Coutinho et al.

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