Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification of the gene causing mucolipidosis type IV

Nature Genetics volume 26, pages 118–122 (2000)Cite this article

Abstract

Mucolipidosis type IV (MLIV) is an autosomal recessive, neurodegenerative, lysosomal storage disorder1 characterized by psychomotor retardation and ophthalmological abnormalities including corneal opacities, retinal degeneration and strabismus. Most patients reach a maximal developmental level of 12–15 months2. The disease was classified as a mucolipidosis following observations by electron microscopy indicating the lysosomal storage of lipids together with water-soluble, granulated substances1,3,4,5,6. Over 80% of the MLIV patients diagnosed are Ashkenazi Jews, including severely affected and mildly affected patients3,4. The gene causing MLIV was previously mapped to human chromosome 19p13.2–13.3 in a region of approximately 1 cM (ref. 7). Haplotype analysis in the MLIV gene region of over 70 MLIV Ashkenazi chromosomes indicated the existence of two founder chromosomes among 95% of the Ashkenazi MLIV families: a major haplotype in 72% and a minor haplotype in 23% of the MLIV chromosomes (ref. 7, and G.B., unpublished data). The remaining 5% are distinct haplotypes found only in single patients. The basic metabolic defect causing the lysosomal storage in MLIV has not yet been identified. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MLIV gene structure.
Figure 2: Splice changes of the major MLIV haplotype.
Figure 3: KpnI restriction analysis of the splice mutation in MLIV families.
Figure 4: Presentation of the deletion in the minor MLIV mutation.
Figure 5: Protein sequence analyses of the mucolipin family.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Berman, E.R., Livni, N., Shapira, E. & Merin, I.S. Congenital Cornea clouding with abnormal systemic storage bodies: a new variant of Mucolipidosis . J. Pediatr. 84, 519–526 (1974).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  4. Chitayat, D. et al. Mucolipidosis type IV: clinical manifestations and natural history. Am. J. Med. Genet. 41, 313– 318 (1991).

    Article  CAS  Google Scholar 

  5. Merin, S., Livni, N., Berman, E.R. & Yatziv, S. Mucolipidosis type IV: ocular, systemic and ultrastructural findings. Invest. Ophthal. 14, 437–448 ( 1975).

    CAS  PubMed  Google Scholar 

  6. Goebel, H.H., Kohlschutter, A. & Lenard, H.G. Morphological and chemical biopsy findings in Mucolipidosis type IV. Clin. Neuropathol. 1, 73– 82 (1982).

    CAS  PubMed  Google Scholar 

  7. Slaugenhaupt, S.A. et al. Mapping of the Mucolipidosis type IV gene to chromosome 19p and definition of founder haplotype. Am. J. Hum. Genet. 65, 773–778 (1999).

    Article  CAS  Google Scholar 

  8. Glusman, G. & Lancet, D. GESTALT: a workbench for automatic integration and visualization of large-scale genomic sequence analyses. Bioinformatics 16, 482–483 (2000).

    Article  CAS  Google Scholar 

  9. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

    Article  CAS  Google Scholar 

  10. Solovyev, V. & Salamov, A. The Gene-Finder, computer tools for analysis of human and model organisms genome sequences. Ismb 5, 294–302 ( 1997).

    CAS  PubMed  Google Scholar 

  11. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  12. Bach, G., Zlotogora, J. & Zeigler, M. Lysosomal storage disorders among Jews. in Genetic Diversity Among Jews (eds Bonne-Tamir, B. & Adam, A.) 301–304 (Oxford University Press, New York, 1992).

    Google Scholar 

  13. Kyte, J. & Doolittle, R.F. A simple method for displaying the hydropathyic character of a protein. J. Mol. Biol. 157, 105–132 (1982).

    Article  CAS  Google Scholar 

  14. Rost, B. & Sander, C. Improved prediction of protein secondary structure by use of sequence profiles and neural networks. Proc. Natl Acad. Sci USA 90, 7558–7562 (1993).

    Article  CAS  Google Scholar 

  15. Sessa, A., Ghiggeri, G.M. & Turco, A.E. Autosomal dominant polycystic kidney disease: clinical and genetic aspects. J. Nephrol. 10, 295 –310 (1997).

    CAS  PubMed  Google Scholar 

  16. Pearson, W.R. & Lipman, D.J. Improved tools for biological sequence comparison. Proc. Natl Acad. Sci. USA 85, 2444–2448 (1988).

    Article  CAS  Google Scholar 

  17. Harris, P.C. Autosomal dominant polycystic kidney disease: clues to pathogenesis. Hum. Mol. Genet. 8, 1861–1866 (1999).

    Article  CAS  Google Scholar 

  18. Hofmann, K., Bucher, P., Falquet, L. & Bairoch, A. The PROSITE database, its status in 1999. Nucleic Acids Res. 27, 215–219 (1999).

    Article  CAS  Google Scholar 

  19. Gribskov, M. et al. Profile analysis: detection of distantly related proteins . Proc. Natl Acad. Sci. USA 84, 4355– 4358 (1987).

    Article  CAS  Google Scholar 

  20. Bonfield, J.K., Smith, K.F. & Staden, R. A new DNA sequence assembly program. Nucleic Acids Res. 23, 4992–4999 (1995).

    Article  CAS  Google Scholar 

  21. Higgins, D.G., Thompson, J.D. & Gibson, T.J. Using CLUSTAL for multiple sequence alignments. Methods Enzymol. 266, 383–402 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the MLIV families for cooperation; the referring clinicians; L. Ashworth for the sequence of chromosome 19; and D. Abeliovich and I. Lerer for help. Part of this work was funded by the generous donation of P. Altura for the R. Altura Fund and by a grant from the Mucolipidosis type IV Foundation. Part of this work was funded by an Infrastructure grant of the Israeli Ministry of Science, the Crown Human Genome Center at The Weizmann Institute of Science and the Krupp Foundation.

Author information

Author notes

  1. Ruth Bargal and Nili Avidan: These authors contributed equally to this work.

Authors and Affiliations

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

    Ruth Bargal, Marcia Zeigler, Ayala Frumkin, Annick Raas-Rothschild & Gideon Bach

  2. Department of Molecular Genetics, The Crown Human Genome Center, The Weizmann Institute of Science, Rehovot, Israel

    Nili Avidan, Edna Ben-Asher, Zvia Olender, Gustavo Glusman & Doron Lancet

Authors
  1. Ruth Bargal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nili Avidan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edna Ben-Asher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zvia Olender
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcia Zeigler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ayala Frumkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Annick Raas-Rothschild
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gustavo Glusman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Doron Lancet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gideon Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gideon Bach.

Supplementary information

Sequence

Multiple alignment of the human MLIV protein with three of its homologues (GIF 187 kb)

Table 1

Exon-intron boundary sequences of the MLIV gene (DOC 20 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bargal, R., Avidan, N., Ben-Asher, E. et al. Identification of the gene causing mucolipidosis type IV. Nat Genet 26, 118–122 (2000). https://doi.org/10.1038/79095

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79095

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing