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 Nov;67(5):1110-20. doi: 10.1016/S0002-9297(07)62941-3. Epub 2000 Sep 29.


Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration, and strabismus. Unlike the situation in other lysosomal disorders, the accumulation of heterogeneous storage material observed in MLIV does not result from a block in the catabolic pathways but is due to an ill-defined transport defect in the late steps of endocytosis. With the aim of cloning the MLIV gene, we searched in the 19p13.2-13.3 region, where the locus previously had been assigned by linkage mapping. In this region, we have identified a novel gene that is mutated in all patients with MLIV who were enrolled in our study. One patient was homozygous for the splice-acceptor mutation, and another was homozygous for a deletion removing the first six exons of the gene. In addition, four compound heterozygotes for these two mutations were identified. Haplotype analysis indicates that we have identified the two major founder mutations, which account for >95% of MLIV chromosomes in Ashkenazi Jewish patients. The gene, ML4, encodes a protein named "mucolipidin, " which localizes on the plasma membrane and, in the carboxy-terminal region, shows homologies to polycystin-2, the product of the polycystic kidney disease 2 gene (PKD2) and to the family of transient receptor potential Ca(2+) channels. Mucolipidin is likely to play an important role in endocytosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • COS Cells
  • Cloning, Molecular
  • DNA Mutational Analysis
  • Databases as Topic
  • Exons / genetics
  • Expressed Sequence Tags
  • Fibroblasts
  • Fluorescent Antibody Technique
  • Founder Effect*
  • Haplotypes / genetics
  • Humans
  • Membrane Proteins / analysis
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Molecular Sequence Data
  • Mucolipidoses / genetics*
  • Mutation / genetics*
  • Open Reading Frames / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Sequence Alignment
  • TRPM Cation Channels
  • Transfection
  • Transient Receptor Potential Channels


  • MCOLN1 protein, human
  • Membrane Proteins
  • RNA, Messenger
  • TRPM Cation Channels
  • Transient Receptor Potential Channels