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Gideon Bach - One of the best experts on this subject based on the ideXlab platform.

  • Mucolipidosis Type IV and the mucolipins.
    Biochemical Society Transactions, 2010
    Co-Authors: Gideon Bach, David A Zeevi, Ayala Frumkin, Aviram Kogot-levin
    Abstract:

    MLIV (Mucolipidosis Type IV) is a neurodegeneratIVe lysosomal storage disorder caused by mutations in MCOLN1 , a gene that encodes TRPML1 (mucolipin-1), a member of the TRPML (transient receptor potential mucolipin) cation channels. Two additional homologues are TRPML2 and TRPML3 comprising the TRPML subgroup in the TRP superfamily. The three proteins play apparently key roles along the endocytosis process, and thus their cellular localization varies among the different group members. Thus TRPML1 is localized exclusIVely to late endosomes and lysosomes, TRPML2 is primarily located in the recycling clathrin-independent GPI (glycosylphosphatidylinositol)-anchored proteins and early endosomes, and TRPML3 is primarily located in early endosomes. Apparently, all three proteins9 main physiological function underlies Ca 2+ channelling, regulating the endocytosis process. Recent findings also indicate that the three TRPML proteins form heteromeric complexes at least in some of their cellular content. The physiological role of these complexes in lysosomal function remains to be elucidated, as well as their effect on the pathophysiology of MLIV. Another open question is whether any one of the TRPMLs bears additional function in channel actIVity

  • Mucolipidosis Type IV the effect of increased lysosomal ph on the abnormal lysosomal storage
    Pediatric Research, 2009
    Co-Authors: Aviram Kogotlevin, Marsha Zeigler, Asher Ornoy, Gideon Bach
    Abstract:

    Mucolipidosis Type IV (MLIV) is a neurodegeneratIVe channelopathy that is caused by the deficiency of TRPML1 actIVity, a nonselectIVe cation channel. TRPML1 is a lysosomal membrane protein, and thus, MLIV is a lysosomal storage disorder. The basic, specific function of TRPML1 has not been yet clarified. A recent report (Soyombo AA, Tjon-Kon-Sang S, Rbaibi Y, Bashllari E, Bisceglia J, Muallem S, Kiselyov K: J Biol Chem 281:7294–7301, 2006) indicated that TRPML1 functions as an outwardly proton channel whose function is the prevention of overacidification of these organelles. Thus, in MLIV the lysosomal pH is lower than normal. Furthermore, attempts by these investigators to increase slightly the lysososmal pH with either Nigericin or Chloroquine suggested correctIVe effect of the abnormal storage in MLIV cells. We investigated this approach using these agents with cultured fibroblasts from severely affected and milder patients. Our data indicated that there was no reduction in the total number of storage vesicles by either agent, although Nigericin resulted in a change in the nature of the storage materials, reducing the presence of lamellated substances (lipids) so that the storage vesicles contained predominantly granulated substances. On the other hand, transfection with the normal MCOLN1 cDNA (the gene coding for TRPML1) resulted in the removal of almost all the storage materials.

  • the frequency of Mucolipidosis Type IV in the ashkenazi jewish population and the identification of 3 novel mcoln1 mutations
    Human Mutation, 2005
    Co-Authors: Gideon Bach, Marcia Zeigler, Ruth Bargal, Michael Webb, Joseph Ekstein
    Abstract:

    Mucolipidosis Type IV (MLIV) is a neurodegeneratIVe lysosomal storage disorder that occurs in an increased frequency in the Ashkenazi Jewish (AJ) population. The frequency of the disease in this population has been established by the testing of 66,749 AJ subjects in the Dor Yeshorim program, a unique premarital population-screening program designed for the Orthodox Jewish community. A carrier rate of 0.0104 (95% C.I 0.0097-0.011) was found. The distribution of the 2 AJ founder mutations, namely, c.416-2A>G and c.1_788del, was determined to be 78.15% and 21.85%, respectIVely. Three novel mutations were identified in non-Jewish MLIV patients, a missense mutation c.1207C>T, p.Arg403Cys; a 2bp deletion, c.302_303delTC; and a nonsense, c.235C>T, Gln79X.

  • Mucolipidosis Type IV
    Molecular Genetics and Metabolism, 2001
    Co-Authors: Gideon Bach
    Abstract:

    Mucolipidosis Type IV (MLIV) is a neurodegeneratIVe lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities, including corneal opacities, retinal degeneration, and strabismus. Severely affected as well as milder patients have been described. Over 80% of the MLIV patients are Ashkenazi Jews; the estimated heterozygote frequency in this population is 1/100. The disease is classified as a Mucolipidosis due to the simultaneous lysosomal storage of lipids together with water-soluble substances. A broad spectrum of lipids and acid mucopolysaccharides were identified as the storage substances. Kinetic studies demonstrated that this heterogeneous storage stems from an abnormal endocytosis process in cells from MLIV patients of membrane components from late endosomes to the lysosomes and/or delayed efflux to the Golgi apparatus. The MLIV gene was mapped to chromosome 19p13.2--13.3 where a novel gene, MCOLN1, with MLIV-causing mutations, was identified. Two mutations were found among 95% of the Ashkenazi MLIV alleles, including an intronic acceptor splice-site mutation in 72% of the alleles and a partial gene deletion in 23%. Each of these mutations was associated with a defined haploType in this chromosomal region. Other mutations were mostly identified in single, Ashkenazi and non-Ashkanazi patients, including missense, nonsense nucleotide deletions, and insertions. All mutations but one were identified in patients exhibiting the severe phenoType, an in-frame amino acid deletion was identified in a mild patient. MCOLN1 encodes a 580 aa protein, mucolipin 1, which is a member of a new protein family of unknown function at present, the mucolipins. Mucolipin 1 is a membrane protein with 6 transmembrane domains, a serine lipase, and nuclear localization signal motIVes. The protein shows homology to a group of calcium channels of the TRP/TRPL family. The involvement of this protein in the endocytosis process of membrane components is currently studied. A population screening operation among the Ashkenazi population for the detection of heterozygotes has been started in Israel as a prevention program.

  • identification of the gene causing Mucolipidosis Type IV
    Nature Genetics, 2000
    Co-Authors: Ruth Bargal, Ayala Frumkin, Marcia Zeigler, Nili Avidan, Edna Benasher, Zvia Olender, Annick Raasrothschild, Gustavo Glusman, Doron Lancet, Gideon Bach
    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.

Hanna Fares - One of the best experts on this subject based on the ideXlab platform.

  • escrt dependent cell death in a caenorhabditis elegans model of the lysosomal storage disorder Mucolipidosis Type IV
    Genetics, 2016
    Co-Authors: Julie M Huynh, Hope Dang, Isabel A Munoztucker, Marvin Oketch, Ian T Liu, Savannah Perno, Natasha Bhuyan, Allison Crain, Ivan A Borbon, Hanna Fares
    Abstract:

    Mutations in MCOLN1, which encodes the cation channel protein TRPML1, result in the neurodegeneratIVe lysosomal storage disorder Mucolipidosis Type IV. Mucolipidosis Type IV patients show lysosomal dysfunction in many tissues and neuronal cell death. The ortholog of TRPML1 in Caenorhabditis elegans is CUP-5; loss of CUP-5 results in lysosomal dysfunction in many tissues and death of developing intestinal cells that results in embryonic lethality. We previously showed that a null mutation in the ATP-Binding Cassette transporter MRP-4 rescues the lysosomal defect and embryonic lethality of cup-5(null) worms. Here we show that reducing levels of the Endosomal Sorting Complex Required for Transport (ESCRT)-associated proteins DID-2, USP-50, and ALX-1/EGO-2, which mediate the final de-ubiquitination step of integral membrane proteins being sequestered into late endosomes, also almost fully suppresses cup-5(null) mutant lysosomal defects and embryonic lethality. Indeed, we show that MRP-4 protein is hypo-ubiquitinated in the absence of CUP-5 and that reducing levels of ESCRT-associated proteins suppresses this hypo-ubiquitination. Thus, increased ESCRT-associated de-ubiquitinating actIVity mediates the lysosomal defects and corresponding cell death phenoTypes in the absence of CUP-5.

  • Mucolipidosis Type IV protein trpml1 dependent lysosome formation
    Traffic, 2015
    Co-Authors: Austin Miller, Ellen Spooner, Brooke M Mclaughlin, Cameron Upchurch, Jessica Schafer, Julie Huynh, Sebastian Hernandez, Liam Oden, Hanna Fares
    Abstract:

    Lysosomes are dynamic organelles that undergo cycles of fusion and fission with themselves and with other organelles. Following fusion with late endosomes to form hybrid organelles, lysosomes are reformed as discrete organelles. This lysosome reformation or formation is a poorly understood process that has not been systematically analyzed and that lacks known regulators. In this study, we quantitatIVely define the multiple steps of lysosome formation and identify the first regulator of this process.

  • systematic screens for proteins that interact with the Mucolipidosis Type IV protein trpml1
    PLOS ONE, 2013
    Co-Authors: Ellen Spooner, Brooke M Mclaughlin, Talya Lepow, Tyler Durns, Justin Randall, Cameron Upchurch, Katherine Miller, Erin M Campbell, Hanna Fares
    Abstract:

    Mucolipidosis Type IV is a lysosomal storage disorder resulting from mutations in the MCOLN1 gene, which encodes the endosomal/lysosomal Transient Receptor Potential channel protein mucolipin-1/TRPML1. Cells isolated from Mucolipidosis Type IV patients and grown in vitro and in in vIVo models of this disease both show several lysosome-associated defects. However, it is still unclear how TRPML1 regulates the transport steps implicated by these defects. Identifying proteins that associate with TRPML1 will facilitate the elucidation of its cellular and biochemical functions. We report here two saturation screens for proteins that interact with TRPML1: one that is based on immunoprecipitation/mass spectrometry and the other using a genetic yeast two-hybrid approach. From these screens, we identified largely non-overlapping proteins, which represent potential TRPML1-interactors., Using additional interaction assays on some of the potential interactors from each screen, we validated some proteins as candidate TRPML1 interactors In addition, our analysis indicates that each of the two screens not only identified some false-positIVe interactors, as expected from any screen, but also failed to uncover potential TRPML1 interactors. Future studies on the true interactors, first identified in these screens, will help elucidate the structure and function of protein complexes containing TRPML1.

  • suppression of the cup 5 Mucolipidosis Type IV related lysosomal dysfunction by the inactIVation of an abc transporter in c elegans
    Development, 2006
    Co-Authors: Lara Schaheen, Greg Patton, Hanna Fares
    Abstract:

    Mutations in MCOLN1, which encodes the protein mucolipin 1, result in the lysosomal storage disease Mucolipidosis Type IV. Studies on human mucolipin 1 and on CUP-5, the Caenorhabditis elegans ortholog of mucolipin 1, have shown that these proteins are required for lysosome biogenesis/function. Loss of CUP-5 results in a defect in lysosomal degradation, leading to embryonic lethality. We have identified a mutation in the ABC transporter MRP-4 that rescues the degradation defect and the corresponding lethality, owing to the absence of CUP-5. MRP-4 localizes to endocytic compartments and its levels are elevated in the absence of CUP-5. These results indicate that the lysosomal degradation defect is exacerbated in some cells because of the accumulation of MRP-4 in lysosomes rather than the loss of CUP-5 per se. We also show that under some conditions, loss of MRP-4 rescues the embryonic lethality caused by the loss of the cathepsin L protease, indicating that the accumulation of ABC transporters may be a more general mechanism whereby an initial lysosomal dysfunction is more severely compromised.

  • basis of lethality in c elegans lacking cup 5 the Mucolipidosis Type IV orthologue
    Developmental Biology, 2006
    Co-Authors: Lara Schaheen, Hope Dang, Hanna Fares
    Abstract:

    Abstract Mutations in MCOLN1 , which encodes the protein h-mucolipin-1, result in the lysosomal storage disease Mucolipidosis Type IV. Studies on CUP-5, the human orthologue of h-mucolipin-1 in Caenorhabditis elegans , have shown that these proteins are required for lysosome biogenesis. We show here that the lethality in cup-5 mutant worms is due to two defects, starvation of embryonic cells and general developmental defects. Starvation leads to apoptosis through a CED-3-mediated pathway. We also show that providing worms with a lipid-soluble metabolite partially rescues the embryonic lethality but has no effect on the developmental defects, the major cause of the lethality. These results indicate that supplementing the metabolic deficiency of Mucolipidosis Type IV patients may not be sufficient to alleviate the symptoms due to tissue degeneration.

Kirill Kiselyov - One of the best experts on this subject based on the ideXlab platform.

  • early evidence of delayed oligodendrocyte maturation in the mouse model of Mucolipidosis Type IV
    Disease Models & Mechanisms, 2020
    Co-Authors: Molly Mepyans, Susan A Slaugenhaupt, Yulia Grishchuk, Livia Andrzejczuk, Jahree Sosa, Sierra Smith, Shawn Herron, Samantha Derosa, Albert L Misko, Kirill Kiselyov
    Abstract:

    ABSTRACT Mucolipidosis Type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitIVe impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white-matter abnormalities, accumulation of undegraded intracellular ‘storage’ material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. The Mcoln1−/− mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here, we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp and Mobp in the Mcoln1−/− cortex, manifesting as early as 10 days after birth and persisting later in life. Such delays were less pronounced in the cerebellum. Despite our previous finding of diminished accumulation of the ferritin-bound iron in the Mcoln1−/− brain, we report no significant changes in expression of the cytosolic iron reporters, suggesting that iron-handling deficits in MLIV occur in the lysosomes and do not involve broad iron deficiency. These data demonstrate very early deficits of oligodendrocyte maturation and critical regional differences in myelination between the forebrain and cerebellum in the mouse model of MLIV. Furthermore, they establish quantitatIVe readouts of the MLIV impact on early brain development, useful to gauge efficacy in pre-clinical trials.

  • loss of trpml1 promotes production of reactIVe oxygen species is oxidatIVe damage a factor in Mucolipidosis Type IV
    Biochemical Journal, 2014
    Co-Authors: Jessica Coblentz, Claudette M St Croix, Kirill Kiselyov
    Abstract:

    TRPML1 (transient receptor potential mucolipin 1) is a lysosomal ion channel permeable to cations, including Fe2+. Mutations in MCOLN1, the gene coding for TRPML1, cause the LSD (lysosomal storage disease) MLIV (Mucolipidosis Type IV). The role of TRPML1 in the cell is disputed and the mechanisms of cell deterioration in MLIV are unclear. The demonstration of Fe2+ buildup in MLIV cells raised the possibility that TRPML1 dissipates lysosomal Fe2+ and prevents its accumulation. Since Fe2+ catalyses the production of ROS (reactIVe oxygen species), we set out to test whether or not the loss of TRPML1 promotes ROS production by Fe2+ trapped in lysosomes. Our data show that RPE1 (retinal pigmented epithelial 1) cells develop a punctate mitochondrial phenoType within 48 h of siRNA-induced TRPML1-KD (knockdown). This mitochondrial fragmentation was aggravated by Fe2+ exposure, but was reversed by incubation with the ROS chelator α-Toc (α-tocopherol). The exposure of TRPML1-KD cells to Fe2+ led to loss of ΔΨm (mitochondrial membrane potential), ROS buildup, lipid peroxidation and increased transcription of genes responsIVe to cytotoxic oxidatIVe stress in TRPML1-KD cells. These data suggest that TRPML1 redistributes Fe2+ between the lysosomes and the cytoplasm. Fe2+ buildup caused by TRPML1 loss potentiates ROS production and leads to mitochondrial deterioration. Beyond suggesting a new model for MLIV pathogenesis, these data show that TRPML1's role in the cell extends outside lysosomes.

  • loss of lysosomal ion channel transient receptor potential channel mucolipin 1 trpml1 leads to cathepsin b dependent apoptosis
    Journal of Biological Chemistry, 2012
    Co-Authors: Grace Colletti, James Quinn, Mark T. Miedel, Ora A. Weisz, Neel Andharia, Kirill Kiselyov
    Abstract:

    Mucolipidosis Type IV (MLIV) is a lysosomal storage disease caused by mutations in the gene MCOLN1, which codes for the transient receptor potential family ion channel TRPML1. MLIV has an early onset and is characterized by developmental delays, motor and cognitIVe deficiencies, gastric abnormalities, retinal degeneration, and corneal cloudiness. The degeneratIVe aspects of MLIV have been attributed to cell death, whose mechanisms remain to be delineated in MLIV and in most other storage diseases. Here we report that an acute siRNA-mediated loss of TRPML1 specifically causes a leak of lysosomal protease cathepsin B (CatB) into the cytoplasm. CatB leak is associated with apoptosis, which can be prevented by CatB inhibition. Inhibition of the proapoptotic protein Bax prevents TRPML1 KD-mediated apoptosis but does not prevent cytosolic release of CatB. This is the first evidence of a mechanistic link between acute TRPML1 loss and cell death.

  • trpml transporters of metals in lysosomes essential for cell survIVal
    Cell Calcium, 2011
    Co-Authors: Kirill Kiselyov, Grace Colletti, Austen Terwilliger, Kathleen Ketchum, Christopher W P Lyons, James Quinn, Shmuel Muallem
    Abstract:

    Key aspects of lysosomal function are affected by the ionic content of the lysosomal lumen and, therefore, by the ion permeability in the lysosomal membrane. Such functions include regulation of lysosomal acidification, a critical process in delIVery and actIVation of the lysosomal enzymes, release of metals from lysosomes into the cytoplasm and the Ca2+-dependent component of membrane fusion events in the endocytic pathway. While the basic mechanisms of lysosomal acidification have been largely defined, the lysosomal metal transport system is not well understood. TRPML1 is a lysosomal ion channel whose malfunction is implicated in the lysosomal storage disease Mucolipidosis Type IV. Recent evidence suggests that TRPML1 is involved in Fe2+, Ca2+ and Zn2+ transport across the lysosomal membrane, ascribing novel physiological roles to this ion channel, and perhaps to its relatIVes TRPML2 and TRPML3 and illuminating poorly understood aspects of lysosomal function. Further, alterations in metal transport by the TRPMLs due to mutations or environmental factors may contribute to their role in the disease phenoType and cell death.

  • Control or TRP-ML1 siRNA–treated (5 d) HeLa cells (A) or fibroblasts (B) were preloaded for 12 h with Alexa Fluor 647–conjugated dextran
    2011
    Co-Authors: Mark T. Miedel, Grace Colletti, Youssef Rbaibi, Christopher J. Guerriero, Kelly M. Weixel, Ora A. Weisz, Kirill Kiselyov
    Abstract:

    Cells were incubated with DiI-LDL on ice for 60 min and were subsequently chased in prewarmed media at 37°C for an additional 30 or 120 min. At the indicated time points, cells were fixed and processed for immunofluorescence. DelIVery of DiI-LDL to lysosomes in cells was measured by quantifying the percent overlap between DiI-LDL and the preloaded Alexa Fluor 647–dextran. Graphical representations of the quantifications are shown (A and B, right) and are expressed as the percent overlap ± SEM for cells under each condition ( = 20). Bars, 10 μm.Copyright information:Taken from "Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for Mucolipidosis Type IV pathogenesis"The Journal of Experimental Medicine 2008;205(6):1477-1490.Published online 9 Jun 2008PMCID:PMC2413042.

Ehud Goldin - One of the best experts on this subject based on the ideXlab platform.

  • Mucolipidosis Type IV part i
    TRP Channels as Therapeutic Targets#R##N#From Basic Science to Clinical Use, 2015
    Co-Authors: Ehud Goldin
    Abstract:

    Abstract Mucolipidosis IV is a neurodevelopmental disorder caused by mutations in the MCOLN1 gene that encodes a transient receptor potential (TRP) nonselectIVe cation channel called mucolipin1 or TRPML1. It affects primarily the brain, the motor system, and the eyes. Typically, patients remain at a very early developmental age and suffer from severe brain hypo- or dysmyelination. They are unable to walk independently and cannot speak either. Moreover, their vision deteriorates during the first decade of life due to loss of retinal function. Many patients’ cell Types contain large endolysosomal vacuoles, accumulating a variety of metabolites including metal ions, lipids, sugars, and proteins. Those vacuoles, although prominent, do not correlate directly with the functionality of the tissue. The only clinically evident biochemical deficit in MLIV is inability to produce stomach acid, probably caused by a deficit in regulated exocytosis. The function of mucolipin is still unknown, and there is still no explanation as to the cause of the disease phenoType.

  • Mucolipidosis Type IV an update
    Molecular Genetics and Metabolism, 2011
    Co-Authors: Kazuyo Wakabayashi, Ann Marie Gustafson, Ellen Sidransky, Ehud Goldin
    Abstract:

    Mucolipidosis Type IV (MLIV) is a neurodevelopmental as well as neurodegeneratIVe disorder with severe psychomotor developmental delay, progressIVe visual impairment, and achlorydria. It is characterized by the presence of lysosomal inclusions in many cell Types in patients. MLIV is an autosomal recessIVe disease caused by mutations in MCOLN1, which encodes for mucolipin-1, a member of the transient receptor potential (TRP) cation channel family. Although approximately 70-80% of patients identified are Ashkenazi Jewish, MLIV is a pan-ethnic disorder. Importantly, while MLIV is thought to be a rare disease, its frequency may be greater than currently appreciated, for its common presentation as a cerebral palsy-like encephalopathy can lead to misdiagnosis. Moreover, patients with milder variants are often not recognized as having MLIV. This review provides an update on the ethnic distribution, clinical manifestations, laboratory findings, methods of diagnosis, molecular genetics, differential diagnosis, and treatment of patients with MLIV. An enhanced awareness of the manifestations of this disorder may help to elucidate the true frequency and range of symptoms associated with MLIV, providing insight into the pathogenesis of this multi-system disease.

  • Mucolipidosis Type IV: A Subtle Pediatric NeurodegeneratIVe Disorder
    Pediatric neurology, 2010
    Co-Authors: Joseph S. Geer, Ehud Goldin, Steve A. Skinner, Kenton R. Holden
    Abstract:

    The mucolipidoses are a heterogeneous group of autosomal recessIVe neurodegeneratIVe lysosomal storage disorders. Mucolipidosis Type IV is rare; it is seen predominantly in the Ashkenazi Jewish population and usually presents with global neurodevelopmental delays in infancy, subtle corneal opacifications or clouding, and very slowly progressIVe neurodegeneration over many years. Elevation of serum gastrin is reported; findings from x-rays of bone and joints and lysosomal studies are normal. Reported here are two cases of Mucolipidosis Type IV in children not of Ashkenazi Jewish origin who presented during infancy with nonspecific global psychomotor delays, generalized hypotonia, and mild corneal abnormalities, but remained undiagnosed for years. A rare gene mutation in MCOLN1 was confirmed in one of the two patients, in addition to abnormal serum gastrin levels. More striking was the length of time that these children eluded detection of their final diagnosis.

  • Mucolipidosis Type IV in a Turkish boy associated with a novel MCOLN1 mutation.
    Brain & development, 2008
    Co-Authors: Beyhan Tüysüz, Ehud Goldin, Baris Metin, Baris Korkmaz, Cengiz Yalcinkaya
    Abstract:

    Mucolipidosis Type IV is a rare neurodegeneratIVe lysosomal storage disorder that usually presents during the first year of life with severe mental retardation, delayed motor milestones and corneal opacities. Mucolipidosis IV is caused by mutations in MCOLN1, a gene encoding mucolipin-1 which is responsible for maintaining lysosomal function. The majority of known patients with this disorders are Ashkenazi Jews, and most have a splice IVS3-2 A>G, or a 6.4 kb deletion mutation in MCOLN1. Here, we present a Turkish patient who, in addition to the typical neurological and visceral characteristics of Mucolipidosis Type IV, also demonstrates defects in the posterior limb of internal capsule by MRI, micrognathia and clinodactyly of the fifth fingers. Direct sequencing of his DNA revealed a homozygous c.1364C>T (S456L) mutation in MCOLN1, which was heterozygous in both consanguineous parents. This mutation, like several previously described, changes the protein sequence in the channel pore domain of the protein. Serine 456 is conserved in mucolipin proteins throughout evolution, therefore the mutation is considered as causatIVe for the severe phenoType of this patient.

  • molecular pathophysiology of Mucolipidosis Type IV ph dysregulation of the mucolipin 1 cation channel
    Human Molecular Genetics, 2004
    Co-Authors: Malay K Raychowdhury, Ehud Goldin, Stefanie Stahl, Silvia Gonzalezperrett, Nicolas Montalbetti, Gustavo A Timpanaro, Bernard Chasan, Wolfgang H Goldmann, Adele Cooney, Horacio F Cantiello
    Abstract:

    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.

Grace Colletti - One of the best experts on this subject based on the ideXlab platform.

  • loss of lysosomal ion channel transient receptor potential channel mucolipin 1 trpml1 leads to cathepsin b dependent apoptosis
    Journal of Biological Chemistry, 2012
    Co-Authors: Grace Colletti, James Quinn, Mark T. Miedel, Ora A. Weisz, Neel Andharia, Kirill Kiselyov
    Abstract:

    Mucolipidosis Type IV (MLIV) is a lysosomal storage disease caused by mutations in the gene MCOLN1, which codes for the transient receptor potential family ion channel TRPML1. MLIV has an early onset and is characterized by developmental delays, motor and cognitIVe deficiencies, gastric abnormalities, retinal degeneration, and corneal cloudiness. The degeneratIVe aspects of MLIV have been attributed to cell death, whose mechanisms remain to be delineated in MLIV and in most other storage diseases. Here we report that an acute siRNA-mediated loss of TRPML1 specifically causes a leak of lysosomal protease cathepsin B (CatB) into the cytoplasm. CatB leak is associated with apoptosis, which can be prevented by CatB inhibition. Inhibition of the proapoptotic protein Bax prevents TRPML1 KD-mediated apoptosis but does not prevent cytosolic release of CatB. This is the first evidence of a mechanistic link between acute TRPML1 loss and cell death.

  • trpml transporters of metals in lysosomes essential for cell survIVal
    Cell Calcium, 2011
    Co-Authors: Kirill Kiselyov, Grace Colletti, Austen Terwilliger, Kathleen Ketchum, Christopher W P Lyons, James Quinn, Shmuel Muallem
    Abstract:

    Key aspects of lysosomal function are affected by the ionic content of the lysosomal lumen and, therefore, by the ion permeability in the lysosomal membrane. Such functions include regulation of lysosomal acidification, a critical process in delIVery and actIVation of the lysosomal enzymes, release of metals from lysosomes into the cytoplasm and the Ca2+-dependent component of membrane fusion events in the endocytic pathway. While the basic mechanisms of lysosomal acidification have been largely defined, the lysosomal metal transport system is not well understood. TRPML1 is a lysosomal ion channel whose malfunction is implicated in the lysosomal storage disease Mucolipidosis Type IV. Recent evidence suggests that TRPML1 is involved in Fe2+, Ca2+ and Zn2+ transport across the lysosomal membrane, ascribing novel physiological roles to this ion channel, and perhaps to its relatIVes TRPML2 and TRPML3 and illuminating poorly understood aspects of lysosomal function. Further, alterations in metal transport by the TRPMLs due to mutations or environmental factors may contribute to their role in the disease phenoType and cell death.

  • Control or TRP-ML1 siRNA–treated (5 d) HeLa cells (A) or fibroblasts (B) were preloaded for 12 h with Alexa Fluor 647–conjugated dextran
    2011
    Co-Authors: Mark T. Miedel, Grace Colletti, Youssef Rbaibi, Christopher J. Guerriero, Kelly M. Weixel, Ora A. Weisz, Kirill Kiselyov
    Abstract:

    Cells were incubated with DiI-LDL on ice for 60 min and were subsequently chased in prewarmed media at 37°C for an additional 30 or 120 min. At the indicated time points, cells were fixed and processed for immunofluorescence. DelIVery of DiI-LDL to lysosomes in cells was measured by quantifying the percent overlap between DiI-LDL and the preloaded Alexa Fluor 647–dextran. Graphical representations of the quantifications are shown (A and B, right) and are expressed as the percent overlap ± SEM for cells under each condition ( = 20). Bars, 10 μm.Copyright information:Taken from "Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for Mucolipidosis Type IV pathogenesis"The Journal of Experimental Medicine 2008;205(6):1477-1490.Published online 9 Jun 2008PMCID:PMC2413042.

  • (A) Control and TRP-ML1 siRNA–treated cells were loaded with 2 μg/ml LacCer for 15 min at 37°C and LysoTracker Red to label lysosomes, as described in Materials and methods
    2011
    Co-Authors: Mark T. Miedel, Grace Colletti, Youssef Rbaibi, Christopher J. Guerriero, Kelly M. Weixel, Ora A. Weisz, Kirill Kiselyov
    Abstract:

    Bar, 10 μm. (B) Where indicated, cells were incubated with 10 μM BAPTA-AM for 1 h. DelIVery of LacCer to lysosomes was measured by quantifying the percent overlap between LacCer and LysoTracker. Data are mean ± SEM. *, P = 0.013 (obtained in six separate measurements).Copyright information:Taken from "Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for Mucolipidosis Type IV pathogenesis"The Journal of Experimental Medicine 2008;205(6):1477-1490.Published online 9 Jun 2008PMCID:PMC2413042.

  • Control or TRP-ML1 siRNA–treated (5 d) HeLa cells were loaded with 3 mg/ml of FITC- and TMR-conjugated dextrans for 12 h
    2011
    Co-Authors: Mark T. Miedel, Grace Colletti, Youssef Rbaibi, Christopher J. Guerriero, Kelly M. Weixel, Ora A. Weisz, Kirill Kiselyov
    Abstract:

    Lysosomal pH was determined by calculating the ratio of TMR/FITC fluorescence. Images were acquired as described in Materials and methods. Ratiometric data were converted to absolute values of pH using TMR/FITC ratios determined from permeabilized cells equilibrated with calibration solutions. Data from 20 random fields of cells were quantified, and the pH determined is presented as mean pH ± SEM. Similar results were obtained in four independent experiments.Copyright information:Taken from "Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for Mucolipidosis Type IV pathogenesis"The Journal of Experimental Medicine 2008;205(6):1477-1490.Published online 9 Jun 2008PMCID:PMC2413042.