Journal of mucopolysaccharidosis and rare diseases

Association for Research of MPS and Rare Diseases (뮤코다당증연구학회)
권호 표지
DOI QR코드

DOI QR Code

Molecular Genetics and Diagnostic Approach of Mucolipidosis II/III

  • Sohn, Young Bae (Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine)
  • Received : 2016.06.08
  • Accepted : 2016.06.16
  • Published : 2016.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Mucolipidosis (ML) II/III are autosomal recessive diseases caused by deficiency of post-translational modification of lysosomal enzymes. The mannose-6-phosphate (M6P) residue in lysosomal enzymes synthesized by N-acetylglucosamine 1-phosphotransferase (GlcNAc-phosphotransferase) serves as recognition marker for trafficking in lysosomes. GlcNAc-phosphotransferase is encoded by GNPTAB and GNPTG. Mutations in GNPTAB cause severe ML II alpha/beta and the attenuated ML III alpha/beta. Whereas mutations in GNPTG cause the ML III gamma, the attenuated type of ML III variant. For the diagnostic approaches, increased urinary oligosaccharides excretion could be a screening test in clinically suspicious patients. To confirm the diagnosis, instead of measuring the activity of GlcNAc phosphotransferase, measuring the enzymatic activities of different lysosomal hydrolases are useful for diagnosis. The activities of several lysosomal hydrolases are decreased in fibroblasts but increased in serum of the patients. In addition, the sequence analysis of causative gene is warranted. Therefore, the confirmatory diagnosis requires a combination of clinical evaluation, biochemical and molecular genetic testing. ML II/III show complex disease manifestations with lysosomal storage as the prime cellular defect that initiates consequential organic dysfunctions. As there are no specific therapy for ML to date, understanding the molecular pathogenesis can contribute to develop new therapeutic approaches ultimately.

Keywords

References

  1. Kornfeld S, Sly WS. I-cell disease and pseudo-Hurler polydystrophy: disorders of lysosomal enzyme phosphorylation and localization, In: Scriver CR, Beaudet AL, Sly WS, Valle D (Eds.). The Metabolic and Molecular Bases of Inherited Disease, vol. III, McGraw-Hill, New York, 2001;3469-505.
  2. Bao M, Booth JL, Elmendorf BJ, Canfield WM. Bovine UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine- 1-phosphotransferase. I. Purification and subunit structure. J Biol Chem 1996;271:31437-45. https://doi.org/10.1074/jbc.271.49.31437
  3. Raas-Rothschild A, Cormier-Daire V, Bao M, et al. Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC). J Clin Invest 2000;105:673-81. https://doi.org/10.1172/JCI5826
  4. Kudo M, Bao M, D’Souza A, et al. The alpha- and beta-subunits of the human UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase [corrected] are encoded by a single cDNA. J Biol Chem 2005;280:36141-9. https://doi.org/10.1074/jbc.M509008200
  5. Otomo T, Muramatsu T, Yorifuji T, et al. Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation. J Hum Genet 2009;54:145-51. https://doi.org/10.1038/jhg.2009.3
  6. Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of nonlysosomal proteins. Biochim Biophys Acta 2009;1793:710-25. https://doi.org/10.1016/j.bbamcr.2008.11.015
  7. Hasilik A, Waheed A, von Figura K. Enzymatic phosphorylation of lysosomal enzymes in the presence of UDP-Nacetylglucosamine. Absence of the activity in I-cell fibroblasts. Biochem Biophys Res Commun 1981;98:761-7. https://doi.org/10.1016/0006-291X(81)91177-3
  8. Kornfeld R, Bao M, Brewer K, Noll C, Canfield WM. Purification and multimeric structure of bovine N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase. J Biol Chem 1998;273:23203-10. https://doi.org/10.1074/jbc.273.36.23203
  9. Ghosh P, Dahms NM, Kornfeld S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 2003;4:202-12. https://doi.org/10.1038/nrm1050
  10. Tiede S, Storch S, Lubke T, et al. Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nat Med 2005;11:1109-12. https://doi.org/10.1038/nm1305
  11. Bargal R, Zeigler M, Abu-Libdeh B, et al. When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet Metab 2006;88:359-63. https://doi.org/10.1016/j.ymgme.2006.03.003
  12. Little LE, Mueller OT, Honey NK, Shows TB, Miller AL. Heterogeneity of N-acetylglucosamine 1-phosphotransferase within mucolipidosis III. J Biol Chem 1986;261:733-8.
  13. Lee WS, Payne BJ, Gelfman CM, Vogel P, Kornfeld S. Murine UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase lacking the gamma-subunit retains substantial activity toward acid hydrolases. J Biol Chem 2007;282:27198-203. https://doi.org/10.1074/jbc.M704067200
  14. Braulke T, Pohl S, Storch S. Molecular analysis of the GlcNac- 1-phosphotransferase. J Inherit Metab Dis 2008;31:253-7. https://doi.org/10.1007/s10545-008-0862-5
  15. Leroy JG, Demars RI. Mutant enzymatic and cytological phenotypes in cultured human fibroblasts. Science 1967;157:804-6. https://doi.org/10.1126/science.157.3790.804
  16. Saul RA, Proud V, Taylor HA, Leroy JG, Spranger J. Prenatal mucolipidosis type II (I-cell disease) can present as Pacman dysplasia. Am J Med Genet A 2005;135:328-32.
  17. Steet RA, Hullin R, Kudo M, et al. A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy. Am J Med Genet A 2005;132a:369-75. https://doi.org/10.1002/ajmg.a.30498
  18. Umehara F, Matsumoto W, Kuriyama M, Sukegawa K, Gasa S, Osame M. Mucolipidosis III (pseudo-Hurler polydystrophy); clinical studies in aged patients in one family. J Neurol Sci 1997;146:167-72. https://doi.org/10.1016/S0022-510X(96)00301-2
  19. Varki AP, Reitman ML, Kornfeld S. Identification of a variant of mucolipidosis III (pseudo-Hurler polydystrophy): a catalytically active N-acetylglucosaminylphosphotransferase that fails to phosphorylate lysosomal enzymes. Proc Natl Acad Sci U S A 1981;78:7773-7. https://doi.org/10.1073/pnas.78.12.7773