Disease relevance of MCOLN1

• Mutations in the MCOLN1 gene cause mucolipidosis type IV (MLIV), a severely debilitating, autosomal recessive, lysosomal storage disorder [1].
• Mucolipidosis type IV (MLIV) is an autosomal recessive, neurodegenerative, lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities including corneal opacities, retinal degeneration and strabismus [2].
• Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disease characterized by severe psychomotor retardation, achlorhydria, and ophthalmological abnormalities [3].
• 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 [4].
• Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities [5].

High impact information on MCOLN1

• Loss of the human mucolipin-1 gene underlies mucolipidosis type IV (MLIV), a lysosomal storage disease that results in severe developmental neuropathology [6].
• Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog [6].
• Unlike other lysosomal storage diseases, MLIV is not associated with a lack of lysosomal hydrolases; instead, MLIV cells display abnormal endocytosis of lipids and accumulate large vesicles, indicating that a defect in endocytosis may underlie the disease [6].
• The TRPML CUP-5 promotes normal lysosome biogenesis and prevents apoptosis [7].
• Finally, we propose a model that relates the lysosome biogenesis defect in the absence of CUP-5/h-mucolipin-1 to cellular phenotypes in worms and in humans [3].

Chemical compound and disease context of MCOLN1

• Furthermore, dissipation of the acidic lysosomal pH of TRP-ML1(-/-) cells by nigericin or chloroquine reversed the lysosomal storage disease phenotype [8].
• Streptococcus sanguis and type 2 fimbriated Actinomyces naeslundii, which bound terminal sialic acid and Galbeta1-3GalNAc, respectively, recognized only a few SM-SL salivary components, primarily MG2 [9].
• The accumulation of phosphatidylcholine (PC) in cultured fibroblasts of mucolipidosis IV (MLIV) patients was studied by subcellular fractionation on percoll gradients [10].
• Incubation of unfractionated and fractionated whole saliva with antibodies raised against human lactoferrin (hLf), secretory leukocyte protease inhibitor (SLPI), and, to a lesser extent, MG2 (high-molecular-weight mucinous glycoprotein) reduced the HIV-1 inhibitory activity significantly [11].
• Pulse-chase studies were performed to investigate the metabolism of phosphatidylethanolamine (PEA) in cultured fibroblasts from patients with mucolipidosis type IV (MLIV) and normal controls [12].

Biological context of MCOLN1

• We also report the identification of eight new polymorphic markers between D19S406 and D19S912, which allowed us to pinpoint the location of MCOLN1 by haplotype analysis and which will facilitate future fine-mapping in this region [13].
• A physical and transcript map of the MCOLN1 gene region on human chromosome 19p13.3-p13.2 [13].
• As a part of the successful cloning of MCOLN1, we constructed a 1.4-Mb physical map containing 14 BACs and 4 cosmids that encompasses the region surrounding MCOLN1 on human chromosome 19p13.3-p13.2-a region to which linkage or association has been reported for multiple diseases [13].
• The MLIV gene was mapped to chromosome 19p13.2--13.3 where a novel gene, MCOLN1, with MLIV-causing mutations, was identified [14].
• Mutation analysis revealed a homozygous novel mutation of a 34 bp deletion and 3 bp insertion in exon 2 of the MCOLN1 gene, perhaps the reason for this unusual clinical and morphological phenotype [15].

Anatomical context of MCOLN1

• Cells from several tissues in MLIV patients accumulate large vacuoles that are presumed to be lysosomes, but whose exact nature remains to be determined [3].
• MLIV is typified by accumulation of lipids and membranous materials in intracellular organelles, which was hypothesized to be caused by the altered membrane fusion and fission events [8].
• F408del and F465L MLIV mutant proteins show a distribution similar to the wild-type protein, whereas T232P is retained in the endoplasmic reticulum [16].
• We studied the subcellular localization of wild-type and three different mutant forms (T232P, F408del and F465L) of mucolipin by expressing Myc-tagged proteins in HeLa cells [16].
• In addition, we found high sensitivity to chloroquine in cultured fibroblasts from MLIV patients [17].

Associations of MCOLN1 with chemical compounds

• Ethylenediamine (en) solutions of K4Pb9 react with toluene solutions of ML4 (M = Pt, Pd, L = PPh3; M = Ni, L2= COD) and 2,2,2-crypt to give M@Pb12(2-) cluster anions (M = Pt (1), Pd (2), Ni (3)) as the [K(2,2,2-crypt)]+ salts in low (Ni) to good (Pt) yields [18].
• Therefore, we investigated whether MG2 was a selectin ligand [19].
• In addition, the N-terminal amino acid sequence of the larger glycopeptide was found to be part of one of the selected MG2 cDNA clones [20].
• Our previous study of MG2 oligosaccharide structures showed that the termini predominantly carry T, sialyl-T, Lewisx (Lex), sialyl Lex (sLex), lactosamine, and sialyl lactosamine determinants [Prakobphol, A., et al. (1998) Biochemistry 37, 4916-4927] [21].
• Thermodynamic and kinetic data for adduct formation, cis-trans isomerization and redox reactions of ML4 complexes: a case study with rhodium- and iridium-tropp complexes in d8, d9 and d10 valence electron configurations (tropp=dibenzotropylidene phosphanes) [22].

Regulatory relationships of MCOLN1

• TRP-ML1 undergoes proteolytic cleavage that is inhibited by inhibitors of cathepsin B (CatB) and is altered when TRP-ML1 is expressed in CatB-/- cells [23].

Other interactions of MCOLN1

• ML1 channel function was assessed from endosomal vesicles of null (MCOLN1(-/-)) and ML1 over-expressing cells, and liposomes containing the in vitro translated protein [24].
• She inherited a 93bp segment from mitochondrial NADH dehydrogenase 5 (MTND5) from her mother that was inserted in-frame prior to the last nucleotide of exon 2 of MCOLN1 (c.236_237ins93) [25].
• ML1 shows sequence homology and topological similarities with polycystin-2 and other transient receptor potential (Trp) channels [24].

Analytical, diagnostic and therapeutic context of MCOLN1

• The localization of MLIV to chromosome 19 will permit genetic prenatal diagnosis in affected families and will aid in the isolation of the disease gene [26].
• 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 [4].
• Cell fractionation indicated specific loss of acidic lipase activity in TRP-ML1(-/-) cells [8].
• In an enzyme-linked immunosorbent assay, L-selectin chimeras interacted with immobilized MG2 in a Ca2+-dependent manner [19].
• We verified the accuracy and specificity of these assays by showing correct measurement of known quantities of purified MG1 or MG2 added to whole saliva and lack of cross-reactivity between mucins and heterologous antisera on Western blots or in ELISAs [27].

References