The molecular basis of mucolipidosis type IV.
Mucolipidosis Type IV (MLIV) is a lysosomal storage disorder that is characterized by severe neurologic and ophthalmologic abnormalities. It is a progressive disease that usually presents during the first year of life with mental retardation, corneal opacities, and delayed motor milestones. First described in 1974, MLIV is a rare autosomal recessive disease and the majority of patients diagnosed to date are of Ashkenazi Jewish descent. MLIV was originally classified as a lysosomal storage disorder due to the abnormal accumulation of mucopolysaccharides and lipids. Extensive studies in MLIV cells, however, have shown that the abnormal storage is due to a defect in the late endocytic pathway. Positional cloning led to the recent discovery of a novel gene on human chromosome 19, MCOLN1, that is mutated in MLIV. To date 14 independent mutations have been reported in MCOLN1, with two mutations accounting for 95% of the Ashkenazi Jewish MLIV alleles. The identification of the MLIV gene has led to a simple tool for definitive diagnosis and will permit carrier screening in the Ashkenazi Jewish population. MCOLN1 is a new member of the transient receptor potential (TRP) cation channel gene family. The protein encoded by MCOLN1, mucolipin-1, has six predicted transmembrane domains and a putative channel pore. The identification of mutations in MCOLN1 represents the first example of a neurological disease caused by a TRP-related channel. While the function of mucolipin-1 is currently unknown, homology to the TRP superfamily and the recent description of the C. elegans mucolipin-1 homolog allow us to begin to speculate about the role of mucolipin-1 in diverse cellular processes.
Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02115, USA. slaugenh@helix.mgh.harvard.edu
Susan A
SA
Slaugenhaupt
D002888:Chromosomes, Human, Pair 19; D003001:Cloning, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D009081:Mucolipidoses / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels
C416674:MCOLN1 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels