mucolipidoses

Summary

Summary: A group of inherited metabolic diseases characterized by the accumulation of excessive amounts of acid mucopolysaccharides, sphingolipids, and/or glycolipids in visceral and mesenchymal cells. Abnormal amounts of sphingolipids or glycolipids are present in neural tissue. INTELLECTUAL DISABILITY and skeletal changes, most notably dysostosis multiplex, occur frequently. (From Joynt, Clinical Neurology, 1992, Ch56, pp36-7)

Top Publications

  1. Eichelsdoerfer J, Evans J, Slaugenhaupt S, Cuajungco M. Zinc dyshomeostasis is linked with the loss of mucolipidosis IV-associated TRPML1 ion channel. J Biol Chem. 2010;285:34304-8 pubmed publisher
    ..We propose that chelatable zinc accumulation in large lysosomes and membranous vacuoles may contribute to the pathogenesis of the disease and progressive cell degeneration in MLIV patients...
  2. Sun M, Goldin E, Stahl S, Falardeau J, Kennedy J, Acierno J, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9:2471-8 pubmed
    ..The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed. ..
  3. Kiselyov K, Colletti G, Terwilliger A, Ketchum K, Lyons C, Quinn J, et al. TRPML: transporters of metals in lysosomes essential for cell survival?. Cell Calcium. 2011;50:288-94 pubmed publisher
    ..Further, alterations in metal transport by the TRPMLs due to mutations or environmental factors may contribute to their role in the disease phenotype and cell death. ..
  4. Raas Rothschild A, Bargal R, Goldman O, Ben Asher E, Groener J, Toutain A, et al. Genomic organisation of the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTAG) and its mutations in mucolipidosis III. J Med Genet. 2004;41:e52 pubmed
  5. Bargal R, Goebel H, Latta E, Bach G. Mucolipidosis IV: novel mutation and diverse ultrastructural spectrum in the skin. Neuropediatrics. 2002;33:199-202 pubmed
    ..Mutation analysis revealed a homozygous novel mutation of a 34 bp deletion and 3 bp insertion in exon 2 of the MCOLN1 gene, perhaps the reason for this unusual clinical and morphological phenotype...
  6. Bach G. Mucolipidosis type IV. Mol Genet Metab. 2001;73:197-203 pubmed
    ..A population screening operation among the Ashkenazi population for the detection of heterozygotes has been started in Israel as a prevention program...
  7. Raychowdhury M, Gonzalez Perrett S, Montalbetti N, Timpanaro G, Chasan B, Goldmann W, et al. Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel. Hum Mol Genet. 2004;13:617-27 pubmed
    ..The evidence also supports a novel role for cation channels in the acidification and normal endosomal function...
  8. Unger S, Paul D, Nino M, McKay C, Miller S, Sochett E, et al. Mucolipidosis II presenting as severe neonatal hyperparathyroidism. Eur J Pediatr. 2005;164:236-43 pubmed
  9. Tiede S, Storch S, Lübke T, Henrissat B, Bargal R, Raas Rothschild A, et al. Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nat Med. 2005;11:1109-12 pubmed
    ..Our results provide evidence that GNPTA encodes a subunit of GlcNAc-1-phosphotransferase defective in individuals with ML II...

More Information

Publications65

  1. Bargal R, Zeigler M, Abu Libdeh B, Zuri V, Mandel H, Ben Neriah Z, et al. When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet Metab. 2006;88:359-63 pubmed
    ..We suggest that the diseases due to mutations in GNPTA represent a clinical continuum between ML III and ML II, and the classification of these diseases should be based on the age of onset, clinical symptoms, and severity...
  2. LaPlante J, Sun M, Falardeau J, Dai D, Brown E, Slaugenhaupt S, et al. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol Genet Metab. 2006;89:339-48 pubmed
    ..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...
  3. Lima W, Leuba F, Soldati T, Cosson P. Mucolipin controls lysosome exocytosis in Dictyostelium. J Cell Sci. 2012;125:2315-22 pubmed publisher
    ..We speculate that mucolipin attenuates the fusogenic effect of local cytosolic increases in Ca(2+) by dissipating them into the lumen of lysosomal compartments...
  4. Kollmann K, Damme M, Markmann S, Morelle W, Schweizer M, Hermans Borgmeyer I, et al. Lysosomal dysfunction causes neurodegeneration in mucolipidosis II 'knock-in' mice. Brain. 2012;135:2661-75 pubmed publisher
    ..These lysosomal proteins might be a potential target for a valid therapeutic approach for mucolipidosis II disease...
  5. Pryor P, Reimann F, Gribble F, Luzio J. Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. Traffic. 2006;7:1388-98 pubmed
    ..Our data demonstrate that the correct localization of mucolipin-1 and the integrity of its ion pore are essential for its physiological function in the late endocytic pathway. ..
  6. Schaheen L, Dang H, Fares H. Basis of lethality in C. elegans lacking CUP-5, the Mucolipidosis Type IV orthologue. Dev Biol. 2006;293:382-91 pubmed
    ..These results indicate that supplementing the metabolic deficiency of Mucolipidosis Type IV patients mat not be sufficient to alleviate the symptoms due to tissue degeneration...
  7. Jennings J, Zhu J, Rbaibi Y, Luo X, Chu C, Kiselyov K. Mitochondrial aberrations in mucolipidosis Type IV. J Biol Chem. 2006;281:39041-50 pubmed
    ..Deficient Ca2+ homeostasis may represent a common mechanism of degenerative cell death in several lysosomal storage diseases...
  8. Tomatsu S, Okamura K, Maeda H, Taketani T, Castrillon S, Gutierrez M, et al. Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis. 2005;28:187-202 pubmed
    ..This finding suggests that measurement of KS level provides a new diagnostic biomarker in a wide variety of mucopolysaccharidoses and mucolipidoses in addition to MPS IV.
  9. Yogalingam G, Bonten E, van de Vlekkert D, Hu H, Moshiach S, Connell S, et al. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev Cell. 2008;15:74-86 pubmed publisher
    ..Our findings uncover an unexpected mechanism influencing lysosomal exocytosis and argue that exacerbations of this process form the basis for certain genetic diseases...
  10. Venkatachalam K, Long A, Elsaesser R, Nikolaeva D, Broadie K, Montell C. Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell. 2008;135:838-51 pubmed publisher
    ..Since hematopoietic cells in humans are involved in clearance of apoptotic cells, our results raise the possibility that bone marrow transplantation may limit the progression of MLIV...
  11. Flanagan Steet H, Sias C, Steet R. Altered chondrocyte differentiation and extracellular matrix homeostasis in a zebrafish model for mucolipidosis II. Am J Pathol. 2009;175:2063-75 pubmed publisher
    ..These findings highlight the potential of the zebrafish system in studying lysosomal disease pathogenesis...
  12. Robinson C, Baker N, Noble J, King A, David G, Sillence D, et al. The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment. J Inherit Metab Dis. 2002;25:681-93 pubmed
    ..Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease...
  13. Altarescu G, Sun M, Moore D, Smith J, Wiggs E, Solomon B, et al. The neurogenetics of mucolipidosis type IV. Neurology. 2002;59:306-13 pubmed
    ..Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family...
  14. Schiffmann R, Dwyer N, Lubensky I, Tsokos M, Sutliff V, Latimer J, et al. Constitutive achlorhydria in mucolipidosis type IV. Proc Natl Acad Sci U S A. 1998;95:1207-12 pubmed
  15. Marschner K, Kollmann K, Schweizer M, Braulke T, Pohl S. A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism. Science. 2011;333:87-90 pubmed publisher
    ..Thus, S1P functions in the biogenesis of lysosomes, and lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction...
  16. Dong X, Cheng X, Mills E, Delling M, Wang F, Kurz T, et al. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature. 2008;455:992-6 pubmed publisher
    ..We propose that TRPML1 mediates a mechanism by which Fe(2+) is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients...
  17. Vergarajauregui S, Puertollano R. Mucolipidosis type IV: the importance of functional lysosomes for efficient autophagy. Autophagy. 2008;4:832-4 pubmed
    ..These findings corroborate recent evidence indicating that defects in autophagy may be a common feature of many neurodegenerative disorders...
  18. Cathey S, Kudo M, Tiede S, Raas Rothschild A, Braulke T, Beck M, et al. Molecular order in mucolipidosis II and III nomenclature. Am J Med Genet A. 2008;146A:512-3 pubmed publisher
  19. Vergarajauregui S, Oberdick R, Kiselyov K, Puertollano R. Mucolipin 1 channel activity is regulated by protein kinase A-mediated phosphorylation. Biochem J. 2008;410:417-25 pubmed
    ..This paper presents the first example of regulation of a member of the mucolipin family by phosphorylation...
  20. Fares H, Greenwald I. Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet. 2001;28:64-8 pubmed
    ..elegans cup-5 mutant may be a useful model for studying conserved aspects of mucolipin-1 structure and function and for assessing the effects of potential therapeutic compounds...
  21. Pshezhetsky A, Ashmarina M. Lysosomal multienzyme complex: biochemistry, genetics, and molecular pathophysiology. Prog Nucleic Acid Res Mol Biol. 2001;69:81-114 pubmed
    ..The genetic, biochemical, and direct structural studies described here clarify the molecular pathogenic mechanisms of these disorders and suggest new diagnostic tools...
  22. Jansen S, Groener J, Bax W, Poorthuis B. Delayed lysosomal metabolism of lipids in mucolipidosis type IV fibroblasts after LDL-receptor-mediated endocytosis. J Inherit Metab Dis. 2001;24:577-86 pubmed
    ..Our results suggest that the defect in mucolipidosis type IV also affects the low-density lipoprotein-receptor-mediated endocytosis pathway...
  23. Monti E, Preti A, Venerando B, Borsani G. Recent development in mammalian sialidase molecular biology. Neurochem Res. 2002;27:649-63 pubmed
    ..Overall, the availability of the cDNA species encoding mammalian sialidases is an important step leading toward a comprehensive picture of the relationships between the structure and biological function of these enzymes...
  24. Slaugenhaupt S. The molecular basis of mucolipidosis type IV. Curr Mol Med. 2002;2:445-50 pubmed
    ..elegans mucolipin-1 homolog allow us to begin to speculate about the role of mucolipin-1 in diverse cellular processes...
  25. Tomatsu S, Montano A, Oguma T, Dung V, Oikawa H, Gutiérrez M, et al. Validation of disaccharide compositions derived from dermatan sulfate and heparan sulfate in mucopolysaccharidoses and mucolipidoses II and III by tandem mass spectrometry. Mol Genet Metab. 2010;99:124-31 pubmed publisher
    Glycosaminoglycans (GAGs) are accumulated in various organs in both mucopolysaccharidoses (MPS) and mucolipidoses II and III (ML II and III)...
  26. Tomatsu S, Gutierrez M, Ishimaru T, Peña O, Montano A, Maeda H, et al. Heparan sulfate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis. 2005;28:743-57 pubmed
    Glycosaminoglycans are accumulated in both mucopolysaccharidoses (MPS) and mucolipidoses (ML). MPS I, II, III and VII and ML II and ML III patients cannot properly degrade heparan sulphate (HS)...
  27. David Vizcarra G, Briody J, Ault J, Fietz M, Fletcher J, Savarirayan R, et al. The natural history and osteodystrophy of mucolipidosis types II and III. J Paediatr Child Health. 2010;46:316-22 pubmed publisher
    ..To assess the natural history and impact of the secondary bone disease observed in patients with mucolipidosis (ML) II and III...
  28. Micsenyi M, Dobrenis K, Stephney G, Pickel J, Vanier M, Slaugenhaupt S, et al. Neuropathology of the Mcoln1(-/-) knockout mouse model of mucolipidosis type IV. J Neuropathol Exp Neurol. 2009;68:125-35 pubmed publisher
    ..This neuropathological characterization of the Mcoln1(-/-) mouse provides an important step in understanding how mucolipin 1 loss of function affects the CNS and contributes to mucolipidosis type IV disease...
  29. Venugopal B, Mesires N, Kennedy J, Curcio Morelli C, LaPlante J, Dice J, et al. Chaperone-mediated autophagy is defective in mucolipidosis type IV. J Cell Physiol. 2009;219:344-53 pubmed publisher
    ..It is also possible that TRPML1 channel activity may be required for CMA. Understanding the role of TRPML1 in CMA will undoubtedly help to characterize the pathogenesis of MLIV...
  30. Vergarajauregui S, Connelly P, Daniels M, Puertollano R. Autophagic dysfunction in mucolipidosis type IV patients. Hum Mol Genet. 2008;17:2723-37 pubmed publisher
    ..Our data are in agreement with recent evidence showing that autophagic defects may be a common characteristic of many neurodegenerative disorders...
  31. Slaugenhaupt S, Acierno J, Helbling L, Bove C, Goldin E, Bach G, et al. Mapping of the mucolipidosis type IV gene to chromosome 19p and definition of founder haplotypes. Am J Hum Genet. 1999;65:773-8 pubmed
    ..The localization of MLIV to chromosome 19 will permit genetic prenatal diagnosis in affected families and will aid in the isolation of the disease gene...
  32. Treusch S, Knuth S, Slaugenhaupt S, Goldin E, Grant B, Fares H. Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc Natl Acad Sci U S A. 2004;101:4483-8 pubmed
    ..Finally, we propose a model that relates the lysosome biogenesis defect in the absence of CUP-5/h-mucolipin-1 to cellular phenotypes in worms and in humans...
  33. Vergarajauregui S, Martina J, Puertollano R. LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV. J Cell Sci. 2011;124:459-68 pubmed publisher
    ..Overall, our data provide new insight into the molecular mechanisms of MCOLN1 function and suggest a potential role for LAPTMs in MLIV pathogenesis...
  34. Vergarajauregui S, Martina J, Puertollano R. Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1. J Biol Chem. 2009;284:36357-66 pubmed publisher
    ..Overall, our data provide new insight into the molecular mechanisms that regulate MCOLN1 activity. We propose that ALG-2 acts as a Ca(2+) sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway...
  35. Otomo T, Higaki K, Nanba E, Ozono K, Sakai N. Inhibition of autophagosome formation restores mitochondrial function in mucolipidosis II and III skin fibroblasts. Mol Genet Metab. 2009;98:393-9 pubmed publisher
    ..These results show for the first time autophagic and mitochondrial dysfunctions in this disorder...
  36. Lukong K, Elsliger M, Chang Y, Richard C, Thomas G, Carey W, et al. Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex. Hum Mol Genet. 2000;9:1075-85 pubmed
  37. Hinek A, Bodnaruk T, Bunda S, Wang Y, Liu K. Neuraminidase-1, a subunit of the cell surface elastin receptor, desialylates and functionally inactivates adjacent receptors interacting with the mitogenic growth factors PDGF-BB and IGF-2. Am J Pathol. 2008;173:1042-56 pubmed publisher
    ..Furthermore, we provide direct evidence that neuraminidase caused the desialylation of both PDGF and IGF-1 receptors and diminished the intracellular signals induced by the mitogenic ligands PDGF-BB and IGF-2...
  38. Boonen M, van Meel E, Oorschot V, Klumperman J, Kornfeld S. Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes. Mol Biol Cell. 2011;22:1135-47 pubmed publisher
    ..Taken together, our results provide new insights into the mechanisms of the tissue-specific abnormalities seen in mucolipidosis type II...
  39. Gelfman C, Vogel P, Issa T, Turner C, Lee W, Kornfeld S, et al. Mice lacking alpha/beta subunits of GlcNAc-1-phosphotransferase exhibit growth retardation, retinal degeneration, and secretory cell lesions. Invest Ophthalmol Vis Sci. 2007;48:5221-8 pubmed
    ..In this study, retinal function and overall disease were assessed in mice lacking GNPTAB, the gene mutated in patients with ML II...
  40. Godra A, Kim D, D Cruz C. Pathologic quiz case: a 5-day-old boy with hydrops fetalis. Mucolipidoses I (Sialidosis III). Arch Pathol Lab Med. 2003;127:1051-2 pubmed
  41. Goldin E, Cooney A, Kaneski C, Brady R, Schiffmann R. Mucolipidosis IV consists of one complementation group. Proc Natl Acad Sci U S A. 1999;96:8562-6 pubmed
    ..These results indicate that all of our known MLIV patients, regardless of ancestry or severity of the developmental defect, have a single mutated gene...
  42. Kollmann K, Pohl S, Marschner K, Encarnação M, Sakwa I, Tiede S, et al. Mannose phosphorylation in health and disease. Eur J Cell Biol. 2010;89:117-23 pubmed publisher
  43. LaPlante J, Falardeau J, Sun M, Kanazirska M, Brown E, Slaugenhaupt S, et al. 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. 2002;532:183-7 pubmed
    ..With its Ca(2+) permeability and modulation by [Ca(2+)], MLN1 could play a major role in Ca(2+) transport regulating lysosomal exocytosis and potentially other phenomena related to the trafficking of late endosomes and lysosomes...
  44. Bach G, Chen C, Pagano R. Elevated lysosomal pH in Mucolipidosis type IV cells. Clin Chim Acta. 1999;280:173-9 pubmed
  45. De Geest N, Bonten E, Mann L, de Sousa Hitzler J, Hahn C, D AZZO A. Systemic and neurologic abnormalities distinguish the lysosomal disorders sialidosis and galactosialidosis in mice. Hum Mol Genet. 2002;11:1455-64 pubmed
    ..The differences and similarities identified in these sialidosis and GS mice may help to better understand the pathophysiology of these diseases in children and to identify more targeted therapies for each of these diseases...
  46. Raas Rothschild A, Cormier Daire V, Bao M, Genin E, Salomon R, Brewer K, et al. Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC). J Clin Invest. 2000;105:673-81 pubmed
    ..This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition...
  47. LaPlante J, Ye C, Quinn S, Goldin E, Brown E, Slaugenhaupt S, et al. Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV. Biochem Biophys Res Commun. 2004;322:1384-91 pubmed
    ..These processes are disturbed in some types of mucolipidoses and other lysosomal storage disorders, such as mucolipidosis IV (MLIV), a neurological disorder that usually ..
  48. Bargal R, Avidan N, Ben Asher E, Olender Z, Zeigler M, Frumkin A, et al. Identification of the gene causing mucolipidosis type IV. Nat Genet. 2000;26:118-23 pubmed
    ..Thus, positional cloning was an alternative to identify the MLIV gene. We report here the identification of a new gene in this human chromosomal region in which MLIV-specific mutations were identified...
  49. Venugopal B, Browning M, Curcio Morelli C, Varro A, Michaud N, Nanthakumar N, et al. Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV. Am J Hum Genet. 2007;81:1070-83 pubmed
    ..In addition, this model provides an invaluable resource for testing treatment strategies and potential therapies aimed at preventing or ameliorating the abnormal lysosomal storage in this devastating neurological disorder...
  50. Bassi M, Manzoni M, Monti E, Pizzo M, Ballabio A, Borsani G. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet. 2000;67:1110-20 pubmed
    ..Mucolipidin is likely to play an important role in endocytosis...
  51. Cathey S, Leroy J, Wood T, Eaves K, Simensen R, Kudo M, et al. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet. 2010;47:38-48 pubmed publisher
    b>Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose 6-phosphate recognition marker is not synthesised on to lysosomal hydrolases and other glycoproteins...
  52. Vogel P, Payne B, Read R, Lee W, Gelfman C, Kornfeld S. Comparative pathology of murine mucolipidosis types II and IIIC. Vet Pathol. 2009;46:313-24 pubmed publisher
    ..We conclude that mice lacking either alpha/beta or gamma subunits displayed clinical and pathologic features that differed substantially from those reported in humans having mutations in orthologous genes...
  53. Cantiello H, Montalbetti N, Goldmann W, Raychowdhury M, Gonzalez Perrett S, Timpanaro G, et al. Cation channel activity of mucolipin-1: the effect of calcium. Pflugers Arch. 2005;451:304-12 pubmed
    ..The new evidence provides support for a novel role of ML1 cation channels in vesicular acidification and normal endosomal function...
  54. Wakabayashi K, Gustafson A, Sidransky E, Goldin E. Mucolipidosis type IV: an update. Mol Genet Metab. 2011;104:206-13 pubmed publisher
    ..An enhanced awareness of the manifestations of this disorder may help to elucidate the true frequency and range of symptoms associated with MLIV, providing insight into the pathogenesis of this multi-system disease...
  55. Schaheen L, Patton G, Fares H. Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C. elegans. Development. 2006;133:3939-48 pubmed
  56. Bach G, Webb M, Bargal R, Zeigler M, Ekstein J. The frequency of mucolipidosis type IV in the Ashkenazi Jewish population and the identification of 3 novel MCOLN1 mutations. Hum Mutat. 2005;26:591 pubmed
    ..15% and 21.85%, respectively. Three novel mutations were identified in non-Jewish MLIV patients, a missense mutation c.1207C>T, p.Arg403Cys; a 2bp deletion, c.302_303delTC; and a nonsense, c.235C>T, Gln79X...