title: Molecular and computational analyses of genes involved in mannose 6-phosphate independent trafficking.
abstract: 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.
authors.affiliation: INSA, Research and Development Unit, Department of Human Genetics, Porto, Portugal.|IPATIMUP, Porto, Portugal.|Department of Biology, Faculty of Sciences, Porto, Portugal.
authors.forename: M F
authors.initials: MF
authors.lastname: Coutinho
authors.affiliation: Biochemical Genetics Unit, CGMJM, Porto, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Lacerda
authors.affiliation: Biochemical Genetics Unit, CGMJM, Porto, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Pinto
authors.affiliation: Biochemical Genetics Unit, CGMJM, Porto, Portugal.
authors.forename: H
authors.initials: H
authors.lastname: Ribeiro
authors.affiliation: IBMC, Instituto de Biologia Celular e Molecular, Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Macedo-Ribeiro
authors.affiliation: INSA, Research and Development Unit, Department of Human Genetics, Porto, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Castro
authors.affiliation: IPATIMUP, Porto, Portugal.|Department of Biology, Faculty of Sciences, Porto, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Prata
authors.affiliation: INSA, Research and Development Unit, Department of Human Genetics, Porto, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Alves
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D056655:Cathepsin H / Q000378:metabolism; D005962:Glucosylceramidase / Q000378:metabolism; D006801:Humans; D008247:Lysosomes; D008360:Mannosephosphates / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics; D021381:Protein Transport / Q000235:genetics*; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D049231:Saposins / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D021601:trans-Golgi Network / Q000201:enzymology / Q000235:genetics; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002402:Cathepsin D; D056655:Cathepsin H; D005962:Glucosylceramidase; D008360:Mannosephosphates; D008562:Membrane Glycoproteins; D017527:Receptor, IGF Type 2; D049231:Saposins; D051122:Scavenger Receptors, Class B; D013108:Sphingomyelin Phosphodiesterase; D000099183:Sortilin; C483345:PSAP protein, human; C495124:SCARB1 protein, human; C027693:mannose-6-phosphate; C112980:acid sphingomyelinase-1; C534126:CTSH protein, human; C533922:CTSD protein, human
keywords: LIMP-2; M6P independent trafficking; lysosomal storage diseases; sortilin