Cation channel probably playing a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. Could play a major role in Ca(2+) transport regulating lysosomal exocytosis.
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.
Mucolipidosis type IV (MLIV) is an autosomal recessive neurogenetic disorder characterized by developmental abnormalities of the brain and impaired neurological, ophthalmologic and gastric function. Large vacuoles accumulate in various types of cells in MLIV patients. However, the pathophysiology of the disease at the cellular level is still unknown. MLIV is caused by mutations in a recently described gene, MCOLN1, encoding mucolipin-1 (ML1), a 65 kDa protein whose function is also unknown. ML1 shows sequence homology and topological similarities with polycystin-2 and other transient receptor potential (Trp) channels. In this study, we assessed both, whether ML1 has ion channel properties, and whether disease-causing mutations in MCOLN1 have functional differences with the wild-type (WT) protein. ML1 channel function was assessed from endosomal vesicles of null (MCOLN1(-/-)) and ML1 over-expressing cells, and liposomes containing the in vitro translated protein. Evidence from both preparations indicated that WT ML1 is a multiple subconductance non-selective cation channel whose function is inhibited by a reduction of pH. The V446L and DeltaF408 MLIV causing mutations retain channel function but not the sharp inhibition by lowering pH. Atomic force imaging of ML1 channels indicated that changes in pH modified the aggregation of unitary channels. Mutant-ML1 did not change in size on reduction of pH. The data indicate that ML1 channel activity is regulated by a pH-dependent mechanism that is deficient in some MLIV causing mutations of the gene. The evidence also supports a novel role for cation channels in the acidification and normal endosomal function.
Mucolipin-1 (MLN1) is a membrane protein with homology to the transient receptor potential channels and other non-selective cation channels. It is encoded by the MCOLN1 gene, which is mutated in patients with mucolipidosis type IV (MLIV), an autosomal recessive disease that is characterized by severe abnormalities in neurological development as well as by ophthalmologic defects. At the cellular level, MLIV is associated with abnormal lysosomal sorting and trafficking. Here we identify the channel function of human MLN1 and characterize its properties. MLN1 represents a novel Ca(2+)-permeable channel that is transiently modulated by changes in [Ca(2+)]. It is also permeable to Na(+) and K(+). Large unitary conductances were measured in the presence of these cations. 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.
Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2-13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the DROSOPHILA: transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.
The directed movement of cations, atoms or small molecules with a net positive charge, into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.
Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2-13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the DROSOPHILA: transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.
Channel function is transiently modulated by changes in Ca(2+), and inhibited by a reduction of pH; pH changes modify the aggregation state of unitary channels.
CuratedUniProtKB
Pathways
According to KEGG, this protein belongs to the following pathway:
Protein involved in the transport of calcium ions. Calcium is essential for a variety of bodily functions, such as neurotransmission, muscle contraction and proper heart function.
Protein involved in the transport of ions. Such proteins are usually transmembrane and mediate a movement of ions across cell membranes. Transport may be passive (facilitated diffusion; down the electrochemical gradient), or active (against the electrochemical gradient). Active transport requires energy which may come from light, oxidation reactions, ATP hydrolysis, or cotransport of other ions or molecules.
Protein involved in the transport of a molecule (metabolite, protein, etc), a ion or an electron across cell membranes, inside the cell or in a tissue fluid.
Protein which is part of a transmembrane protein complex that forms a hydrophilic channel across the lipid bilayer through which specific inorganic ions can diffuse down their electrochemical gradients. The channels are usually gated and only open in response to a specific stimulus, such as a change in membrane potential (voltage-gated) or the binding of a ligand (ligand-gated channel).
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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