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Mucolipin 1: endocytosis and cation channel—a review

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Abstract

Mucolipidosis type IV (MLIV) is a neurodegenerative, recessive, lysosomal storage disorder characterized by psychomotor retardation and visual impairment due to various ophthalmologic abnormalities. MLIV is found in relatively high frequency in the Ashkenazi Jewish population. The disease is caused by mutations in the gene MCOLN1, which encodes the protein mucolipin 1 (MLN1), a member of the mucolipins family. MLN1 is a non-specific cation channel, and its putative structure attributes it to the TRP superfamily; thus, the gene is also referred as TRPML1. Over 16 MLIV-causing mutations, including two founder mutations in the Ashkenazi population, have been identified hitherto. Atypical increased lysosomal storage in MLIV is present in the cells of all patients. This accumulation is caused by an abnormal endocytosis process of the membrane components to late endosomes to the lysosomes, resulting in an apparent block in the traffic process in pre-lysosomal vacuoles with intraluminal pH of >5.0. MLN1 was localized in cultured cells to late endosomes and lysosomes. The exact function of this cation channel in the late stages of lysosomal maintenance is currently under study.

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References

  1. Altarescu G, Sun M, Moore DR, Smith JA, Wiggs EA, Solomon BI, Patronas NJ, Frei KP, Gupta S, Kaneski CR, et al. (2002) The neurogenetics of Mucolipidosis type IV. Neurology 59:306–313

    CAS  PubMed  Google Scholar 

  2. Amir N, Zlotogora J, Bach G (1987) Mucolipidosis type IV: clinical and natural history. Pediatrics 79:953–959

    CAS  PubMed  Google Scholar 

  3. Bach G (2001) Mucolipidosis type IV. A review. Mol Genet Metab 73:197–203

    Article  CAS  PubMed  Google Scholar 

  4. Bach G, Cohen MM, Kohn G (1975) Abnormal ganglioside accumulation in cultured fibroblasts from patients with mucolipidosis IV. Biochem Biophys Res Commun 66:1483–1490

    CAS  PubMed  Google Scholar 

  5. Bach G, Zeigler M, Kohn G, Cohen MM (1977) Mucopolysaccarides accumulation in cultured skin fibroblasts derived from patients with Mucolipidosis IV. Am J Hum Genet 29:610–618

    CAS  PubMed  Google Scholar 

  6. Bach G, Zeigler M, Kohn G (1980) Biochemical investigations of cultured amniotic fluid cells in mucolipidosis IV. Clin Chim Acta 157:183–190

    Google Scholar 

  7. Bach G, Chen CS, Pagano RE (1999) Abnormal lysosomal pH in mucolipidosis type IV cells. Clin Chim Acta 280:173–179

    Article  CAS  PubMed  Google Scholar 

  8. Bargal R, Bach G (1988) Phospholipids accumulation in mucolipidosis IV cultured fibroblasts. J Inherit Metab Dis 11:144–510

    CAS  PubMed  Google Scholar 

  9. Bargal R, Bach (1997) Mucolipidosis type IV: abnormal transport of lipids to the lysosomes. J Inherit Metab Dis 20:625–632

    Article  CAS  PubMed  Google Scholar 

  10. Bargal R, Avidan N, Ben Asher E, Olender Z, Zeigler M, Frumkin A, Raas-Rothschild A, Glusman G, Lancet D, Bach G (2000) Identification of the gene causing mucolipidosis type IV. Nat Genet 26:118–123

    Article  CAS  PubMed  Google Scholar 

  11. Bargal R, Avidan N, Olender Z, Ben Asher E, Zeigler M, Raas-Rothschild A, Frumkin A, Ben Yosef O, Lancet D, Bach G (2001) Mucolipidosis type IV: Novel mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat 17:397–402

    Article  CAS  PubMed  Google Scholar 

  12. Bassi MT, Manzoni M, Monti E, Pizzo MT, Ballabio A, Borsani G (2000) Cloning of the gene encoding a novel integral membrane protein mucolipin, and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet 67:1110–1120

    CAS  PubMed  Google Scholar 

  13. Berman ER, Livni N, Shapira E, Merin S, Levij IS (1974) Congenital corneal clouding with abnormal systemic storage bodies: a new variant of Mucolipidosis. J Pediat 84:519–526

    CAS  PubMed  Google Scholar 

  14. Caimi L, Tettamanti G, Bera B, Sale FO, Borrone C, Gatti R, Durand P, Martin JJ (1982) Mucolipidosis IV, a sialolipidosis due to ganglioside sialidase deficiency. J Inherit Metab Dis 5:218–224

    CAS  PubMed  Google Scholar 

  15. Casteels I, Taylor DSI, Lake BD, Spalton DT, Bach G (1992) Mucolipidosis IV: presentation of a mild variant. Ophthal Pediatr Genet 13:205–210

    CAS  Google Scholar 

  16. Chen CS, Bach G, Pagano RE (1998) Abnormal transport along the lysosomal pathway in Mucolipidosis type IV disease. Proc Nat Acad Sci USA 95:6373–6378

    Article  CAS  PubMed  Google Scholar 

  17. Chitayat D, Meunier CM, Hodgkinson KA, Silver K, Planters M, Anderson IJ, Little JM, Whiteman DAH, Carpenter S (1991) Mucolipidosis type IV: clinical manifestations and natural history. Am J Med Genet 41:313–318

    Google Scholar 

  18. Crandall BF, Philippart M, Brown WJ, Bluestone D (1982) Mucolipidosis IV. Am J Med Genet 12:301–308

    CAS  PubMed  Google Scholar 

  19. Delmas P (2004) Polycystins: from mechanosensation to gene regulation. Cell 118:145–148

    Article  CAS  PubMed  Google Scholar 

  20. DiPalma F, Belyantseva IA, Kim HJ, Vogt TF, Kachar B, Noben-Tranth K (2002) Mutations in MCOLN3 associated with deafness and pigmentation defects in varitint-wadder (VA) mice. Proc Nat Acad Sci USA 99:14994–14999

    Article  CAS  PubMed  Google Scholar 

  21. Edelmann L, Dong J, Desnick RJ, Kornreich R (2002) Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population. Am J Hum Genet 70:1023–1027

    Article  PubMed  Google Scholar 

  22. Fares H, Greenwald I (2001) Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin 1 homology. Nat Genet 28:64–68

    Article  CAS  PubMed  Google Scholar 

  23. Folkerth Rd, Alroy J, Lomakina I, Skutelsky E, Raghavan SS, Kolodny EH (1995) Mucolipidosis IV: morphology and histochemistry of an autopsy case. J Neuropathol Exp Neurol 54:154–164

    Google Scholar 

  24. Frei KP, Patronas N, Crutchfield KE, Altarescu G, Schiffmann R (1998) Mucolipidosis type IV—characteristic MRI finding. Neurology 51:565–569

    CAS  PubMed  Google Scholar 

  25. Goebel HH, Kohischutter A, Lenard HG (1982) Morphological and chemical biopsy finding in mucolipidosis IV. Clin Neuropathol 1:73–82

    CAS  PubMed  Google Scholar 

  26. Hersh BM, Hartwieg E, Horvitz RH (2002) The Caenorhabditis elegans mucolipin-like gene CUP-5 is essential for viability and regulates lysosomes in multiple cell types. Proc Nat Acad Sci USA 99:4355–4360

    Article  CAS  PubMed  Google Scholar 

  27. Jansen SM, Groener JEM, Bax W, Poorthuis BJHM (2001) Delayed lysosomal metabolism of lipids in mucolipidosis type IV fibroblasts after LDL-receptor-mediated endocytosis. J Inherit Metab Dis 24:577–586

    Article  CAS  PubMed  Google Scholar 

  28. LaPlante JM, Falardeau J, Sun M, Kanazirka M, Brown EM, Slaugenhaupt SA, Vassilev PM (2002) Identification and characterization of the single channel function of human mucolipin-1 implicated in mucolipidosis type IV; a disorder affecting the lysosomal pathway. FEBS Lett 532:183–187

    Article  CAS  PubMed  Google Scholar 

  29. Levitan IB, Cibulsky SM (2001) TRP ion channels: two proteins in one. Science 293:1270–1271

    Article  CAS  PubMed  Google Scholar 

  30. Lubensky IA, Schiffmann R, Goldin E, Tsokos M (1999) Lysosomal inclusions in gastric parietal cells in mucolipidosis type IV: a novel cause of achlorohydria and hypergastremia. Am J Hum Genet 23:1527–1531

    CAS  Google Scholar 

  31. Luzio JP, Poupon V, Lindsay MR, Mullock BM, Piper RC, Pryor PR (2003) Membrane dynamics and the biogenesis of lysosomes. Mol Mem Biol 20:141–154

    Article  CAS  Google Scholar 

  32. Manzoni M, Monti E, Bresciani R, Bozzato A, Barlati S, Bassi MT, Borsani G (2004) Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization. FEBS Lett 567:219–224

    Article  CAS  PubMed  Google Scholar 

  33. Maxfield FR, McGraw TE (2004) Endocytic recycling. Nat Rev Mol Cell Biol 5:121–132

    Article  CAS  PubMed  Google Scholar 

  34. Merin S. Livni N, Berman ER, Yatziv S (1975) Mucolipidosis IV: ocular, systemic and ultrastructural findings. Invest Ophthal 14:437–448

    CAS  PubMed  Google Scholar 

  35. Minke B, Selinger Z (1996) The roles of TRP and calcium in regulating photoreceptor function in Drosophila. Curr Opin Neurobiol 6:459–466

    Article  CAS  PubMed  Google Scholar 

  36. Newell FW, Matalon R, Meyers S (1975) A new mucolipidosis with psychomotor retardation, corneal clouding and retina degeneration. Am J Ophthal 80:440–449

    CAS  PubMed  Google Scholar 

  37. Pagano RE, Puri V, Domingues M, Marks DL (2000) Membrane traffic in sphingolipid storage diseases. Traffic 1:807–815

    Article  CAS  PubMed  Google Scholar 

  38. Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, Blanchette-Mackie EJ, Pentchev PC (2001) Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw Hill, New York, pp 3611–3633

  39. Pryor PR, Mullock BM, Bright NA, Gray SR, Luzio JP (2000) The role of intraorganellar Ca2+ in late endosome-lysosome heterotypic fusion and in the reformation of lysosomes from hybrid organelles. J Cell Biol 149:1053–1062

    Article  CAS  PubMed  Google Scholar 

  40. Raas-Rothschild A, Bargal R, Della-Pergola S, Zeigler M, Bach G (1999) Mucolipidosis type IV: the origin of the disease in the Ashkenazi Jewish population. Eur J Hum Genet 7:496–498

    CAS  PubMed  Google Scholar 

  41. Reiss S, Sheffer R, Merin S, Luder A, Bach G (1993) Mucolipidosis type IV: a late onset and mild form. Am J Med Genet 47:392–394

    PubMed  Google Scholar 

  42. Raychowdhury MK, Gonzalez-Perret S, Montalbetti N, Timpanaro GA, Chasan B, Goldman WH, Stahl S, Cooney A, Goldin E, Cantiello HF (2004) Molecular pathophysiology of mucolipidosis type IV: pH dysregulations of the mucolipin-1 cation channel. Hum Mol Genet 13:617–627

    Article  CAS  PubMed  Google Scholar 

  43. Risch N, Tang H, Katzenstein H, Ekstein J (2003) Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection. Am J Hum Genet 72:812–22

    Article  CAS  PubMed  Google Scholar 

  44. Schiffmann R, Dwyer NK, Lubensky IA, Tsokov M, Sultief VE, Latimer JS, Frei KP, Brady RO, Barton NW, Blanchette-Mackie EJ, Goldin E (1998) Constitutive achlorohydria in mucolipidosis type IV. Proc Nat Acad Sci USA 95:1207–1212

    Article  CAS  PubMed  Google Scholar 

  45. Slaugenhaupt SA, Acierno JS, Hebing LA, Bove C, Goldin E, Bach G, Schiffmann R, Guesella JF (1999) Mapping of the mucolipidosis type IV gene to chromosomal 19p and definition of founder haplotypes. Am J Hum Genet 65:773–778

    Article  CAS  PubMed  Google Scholar 

  46. Slaugenhaupt SA (2002) The molecular basis of mucolipidosis type IV. Curr Mol Med 2:445–450

    CAS  PubMed  Google Scholar 

  47. Smith JA, Chan CC, Goldin E, Schiffmann R (2002) Noninvasive diagnosis and ophthalmic features of mucolipidosis type IV. Ophthalmology 109:588–594

    Article  PubMed  Google Scholar 

  48. Sun M, Goldin E, StahL S, Falardeau JL, Kennedy JC, Acierno JS, Bove C, Kanesky CR, Nagle J, Bromely MC, Colman M, Schiffmann R, Slaugenhaupt SA (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet 9:2471–2478

    Article  CAS  PubMed  Google Scholar 

  49. Tellez-Nagel I, Rapin I, Iwamoto T, Johnson AA, Norton WT, Nitowsky H (1976) Mucolipidosis IV: clinical, ultrastructural, histochemical and chemical studies of a case, including a brain biopsy. Arch Neurol 33:828–835

    CAS  PubMed  Google Scholar 

  50. Vruchte D te, Lloyd-Evans E, Veldman RJ, Neville DC, Dwek RA, Platt FM, van Blitterswijk WJ, Sillence DJ (2004) The accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endocytic transport. J Biol Chem 279:26167–26175

    Article  PubMed  Google Scholar 

  51. Treusch S, Knuth S, Slaugenhaupt SA, Goldin E, Grant BD, Fares H (2004) Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosomal biogenesis. Proc Nat Acad Sci USA 101:4483–4488

    Article  CAS  PubMed  Google Scholar 

  52. Zeigler M, Bach G (1986) Internalization of exogenous gangliosides in cultured skin fibroblasts for the diagnosis of mucolipidosis type IV. Clin Chim Acta 157:183–190

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by grants from the Israeli Science Foundation, number 608/01-2, and the Israeli Ministry of Health (chief scientist), number 4983.

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  1. Department of Human Genetics, Hadassah Hebrew University Hospital, 91120, Jerusalem, Israel

    Gideon Bach

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Correspondence to Gideon Bach.

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Bach, G. Mucolipin 1: endocytosis and cation channel—a review. Pflugers Arch - Eur J Physiol 451, 313–317 (2005). https://doi.org/10.1007/s00424-004-1361-7

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