title: Lysosomal exocytosis is impaired in mucolipidosis type IV.
abstract: Mucolipidosis type IV (MLIV) is an autosomal recessive disease characterized by severe neurological impairment, ophthalmologic defects, and gastric dysfunction. MLIV cells have a deficiency in the late endosomal/lysosomal (LEL) pathway that results in the buildup of lysosomal inclusions. Using a Xenopus oocyte expression system, we previously showed that mucolipin-1 (MLN1), the protein encoded by the MCOLN1 gene is a Ca2+ -permeable non-selective cation channel that is transiently modulated by elevations in intracellular Ca2+. We further showed that MLN1 is translocated to the plasma membrane during lysosomal exocytosis. In this study we show that lysosomal exocytosis is impaired in fibroblasts from MLIV patients, indicating that MLN1 plays an active role in this process. Further, we show that transfection with wild type MLN1 cDNA rescues exocytosis, suggesting the possibility of treatments based on the restoration of this crucial cellular function.
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension and Membrane Biology Program, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: LaPlante
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: John
authors.initials: J
authors.lastname: Falardeau
authors.forename: Daisy
authors.initials: D
authors.lastname: Dai
authors.forename: Edward M
authors.initials: EM
authors.lastname: Brown
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
authors.forename: Peter M
authors.initials: PM
authors.lastname: Vassilev
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005089:Exocytosis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D050051:Transient Receptor Potential Channels; D014981:Xenopus; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D015220:Calcium Channels; D018076:DNA, Complementary; D051907:Lysosomal Membrane Proteins; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C416674:MCOLN1 protein, human