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mucolipidosis

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https://www.readbyqxmd.com/read/29773673/lysosomal-proteome-and-secretome-analysis-identifies-missorted-enzymes-and-their-non-degraded-substrates-in-mucolipidosis-iii-mouse-cells
#1
Giorgia Di Lorenzo, Renata Voltolini Velho, Dominic Winter, Melanie Thelen, Shiva Ahmadi, Michaela Schweizer, Raffaella De Pace, Kerstin Cornils, Timur Alexander Yorgan, Saskia Grüb, Irm Hermans-Borgmeyer, Thorsten Schinke, Sven Müller-Loennies, Thomas Braulke, Sandra Pohl
Targeting of soluble lysosomal enzymes requires mannose 6-phosphate (M6P) signals whose formation is initiated by the hexameric N-acetylglucosamine (GlcNAc)-1-phosphotransferase complex (α2β2γ2). Upon proteolytic cleavage by site-1 protease, the α/β-subunit precursor is catalytically activated but the functions of γ-subunits (Gnptg) in M6P modification of lysosomal enzymes are unknown. To investigate this, we analyzed the Gnptg expression in mouse tissues, primary cultured cells, and in Gnptg reporter mice in vivo, and found high amounts in the brain, eye, kidney, femur, vertebra and fibroblasts...
May 17, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29771310/fingolimod-phosphate-inhibits-astrocyte-inflammatory-activity-in-mucolipidosis-iv
#2
Laura Weinstock, Amanda M Furness, Shawn Herron, Sierra S Smith, Sitara Sankar, Samantha G DeRosa, Dadi Gao, Molly E Mepyans, Anna Scotto Rosato, Diego L Medina, Ayelet Vardi, Natalia S Ferreira, Soo Min Cho, Anthony H Futerman, Susan A Slaugenhaupt, Levi B Wood, Yulia Grishchuk
Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathological signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod...
May 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29770442/current-concepts-in-the-neuropathogenesis-of-mucolipidosis-type-iv
#3
REVIEW
Lauren C Boudewyn, Steven U Walkley
Mucolipidosis type IV (MLIV) is an autosomal recessive, lysosomal storage disorder causing progressively severe intellectual disability, motor and speech deficits, retinal degeneration often culminating in blindness, and systemic disease causing a shortened lifespan. MLIV results from mutations in the gene MCOLN1 encoding the transient receptor potential channel mucolipin-1. It is an ultra-rare disease and is currently known to affect just over 100 diagnosed individuals. The last decade has provided a wealth of research focused on understanding the role of the enigmatic mucolipin-1 protein in cell and brain function and how its absence causes disease...
May 16, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29704188/mucolipidosis-type-iii-a-series-of-adult-patients
#4
Esmee Oussoren, David van Eerd, Elaine Murphy, Robin Lachmann, Jan C van der Meijden, Lies H Hoefsloot, Rob Verdijk, George J G Ruijter, Mario Maas, Carla E M Hollak, Janneke G Langendonk, Ans T van der Ploeg, Mirjam Langeveld
BACKGROUND: Mucolipidosis type III α/β or γ (MLIII) are rare autosomal recessive diseases, in which reduced activity of the enzyme UDP-N-acetyl glucosamine-1-phosphotransferase (GlcNAc-PTase) leads to intra-lysosomal accumulation of different substrates. Publications on the natural history of MLIII, especially the milder forms, are scarce. This study provides a detailed description of the disease characteristics and its natural course in adult patients with MLIII. METHODS: In this retrospective chart study, the clinical, biochemical and molecular findings in adult patients with a confirmed diagnosis of MLIII from three treatment centres were collected...
April 27, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29623569/advances-in-computer-assisted-syndrome-recognition-by-the-example-of-inborn-errors-of-metabolism
#5
Jean T Pantel, Max Zhao, Martin A Mensah, Nurulhuda Hajjir, Tzung-Chien Hsieh, Yair Hanani, Nicole Fleischer, Tom Kamphans, Stefan Mundlos, Yaron Gurovich, Peter M Krawitz
Significant improvements in automated image analysis have been achieved in recent years and tools are now increasingly being used in computer-assisted syndromology. However, the ability to recognize a syndromic facial gestalt might depend on the syndrome and may also be confounded by severity of phenotype, size of available training sets, ethnicity, age, and sex. Therefore, benchmarking and comparing the performance of deep-learned classification processes is inherently difficult. For a systematic analysis of these influencing factors we chose the lysosomal storage diseases mucolipidosis as well as mucopolysaccharidosis type I and II that are known for their wide and overlapping phenotypic spectra...
April 5, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29620587/mucolipidosis-type-ii-affecting-1-fetus-and-placental-disk-of-a-dichorionic-diamnionic-twin-gestation-a-case-report-and-review-of-the-literature
#6
David B Chapel, Bonnie Choy, Peter Pytel, Aliya N Husain, Ricardo R Lastra
Mucolipidosis type II, also known as I-cell disease, is an autosomal recessive inborn error of metabolism, resulting from loss-of-function mutations in GNPTAB. Affected infants exhibit multiple physical anomalies and developmental delay, and death from disease follows in early childhood. Here we present an instructive case of mucolipidosis type II affecting 1 fetus and placental disk in a dichorionic-diamnionic twin pregnancy delivered at 36-wk gestation. The second twin and placental disk showed no abnormality...
April 3, 2018: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/29539424/tgf-%C3%A3-regulates-cathepsin-activation-during-normal-and-pathogenic-development
#7
Heather Flanagan-Steet, Courtney Christian, Po-Nien Lu, Megan Aarnio-Peterson, Laura Sanman, Stephanie Archer-Hartmann, Parastoo Azadi, Matthew Bogyo, Richard A Steet
Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ß signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S)...
March 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29464560/transient-receptor-potential-trp-channels
#8
Amrita Samanta, Taylor E T Hughes, Vera Y Moiseenkova-Bell
Transient Receptor Potential (TRP) channels are evolutionarily conserved integral membrane proteins. The mammalian TRP superfamily of ion channels consists of 28 cation permeable channels that are grouped into six subfamilies based on sequence homology (Fig. 6.1). The canonical TRP (TRPC) subfamily is known for containing the founding member of mammalian TRP channels. The vanilloid TRP (TRPV) subfamily has been extensively studied due to the heat sensitivity of its founding member. The melastatin-related TRP (TRPM) subfamily includes some of the few known bi-functional ion channels, which contain functional enzymatic domains...
2018: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/29289611/variants-in-gnptab-gnptg-and-nagpa-genes-are-associated-with-stutterers
#9
Nima Kazemi, Mehrdad Asghari Estiar, Hassan Fazilaty, Ebrahim Sakhinia
Non-syndromic stuttering is a neurodevelopmental disorder characterized by disruptions in normal flow of speech in the form of repetition, prolongation and involuntary halts. Previously, mutations with more severe effects on GNPTAB and GNPTG have been reported to cause Mucolipidosisll (ML-ll) and Mucolipidosislll (ML-lll), two lysosomal storage disorders with multiple pathologies. We used homozygosity mapping and Sanger sequencing to investigate variants of the three genes in 25 Iranian families with at least two first degree related non-syndromic stutterers...
March 20, 2018: Gene
https://www.readbyqxmd.com/read/29218369/peripheral-nerve-ultrasound-findings-in-mucolipidosis-type-3
#10
Eoin Mulroy, Andrew M Chancellor, Luciana Pelosi
PURPOSE: The mucolipidoses are rare autosomal recessive lysosomal storage disorders. Neurologic involvement in these conditions is generally thought to be limited to cognitive delay and entrapment neuropathies (primarily carpal tunnel syndrome). We sought to evaluate peripheral nerves in this condition using nerve ultrasound. METHODS: We performed peripheral nerve ultrasound in two siblings with genetically confirmed mucolipidosis type 3 (alpha/beta). RESULTS: Peripheral nerves in mucolipidosis type 3 (alpha/beta) exhibit multifocal enlargement...
February 2018: Neuroradiology
https://www.readbyqxmd.com/read/29170090/mucolipidosis-type-iii-gamma-three-novel-mutation-and-genotype-phenotype-study-in-eleven-patients
#11
Beyhan Tüysüz, Özgür Kasapçopur, Dilek Uludağ Alkaya, Sezgin Şahin, Betül Sözeri, Gözde Yeşil
Mucolipidosis type III gamma (MLIII gamma) is a lysosomal storage disease characterized by joint stiffness, mild coarse face and corneal clouding, which becomes recognizable usually in childhood. Biallelic mutations in the GNPTG gene, which encode the γ subunit of the N-acetylglucosamine-1-phosphotransferase enzyme, are the underlying cause of MLIII gamma. The aim of this study is to evaluate the longitudinal findings and genotype of eleven patients from eight families with MLIII gamma and to establish a genotype-phenotype correlation...
February 5, 2018: Gene
https://www.readbyqxmd.com/read/29019983/human-trpml1-channel-structures-in-open-and-closed-conformations
#12
Philip Schmiege, Michael Fine, Günter Blobel, Xiaochun Li
Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+ -releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily...
October 19, 2017: Nature
https://www.readbyqxmd.com/read/29019981/structure-of-mammalian-endolysosomal-trpml1-channel-in-nanodiscs
#13
Qingfeng Chen, Ji She, Weizhong Zeng, Jiangtao Guo, Haoxing Xu, Xiao-Chen Bai, Youxing Jiang
Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2 ) binds to the N terminus of the channel-distal from the pore-and the helix-turn-helix extension between segments S2 and S3 probably couples ligand binding to pore opening...
October 19, 2017: Nature
https://www.readbyqxmd.com/read/29019979/cryo-electron-microscopy-structure-of-the-lysosomal-calcium-permeable-channel-trpml3
#14
Marscha Hirschi, Mark A Herzik, Jinhong Wie, Yang Suo, William F Borschel, Dejian Ren, Gabriel C Lander, Seok-Yong Lee
The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily and is composed of three members: TRPML1-TRPML3. TRPMLs are the major Ca2+ -permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca2+ from organelles, which is important for various physiological processes, including organelle trafficking and fusion. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint-waddler (Va) mouse phenotype...
October 19, 2017: Nature
https://www.readbyqxmd.com/read/28950892/next-generation-sequencing-identifies-mutations-in-gnptg-gene-as-a-cause-of-familial-form-of-scleroderma-like-disease
#15
Abdelali Zrhidri, Saadia Amasdl, Jaber Lyahyai, Hanane Elouardi, Bouchra Chkirate, Laure Raymond, Grégory Egéa, Mohamed Taoudi, Said El Mouatassim, Abdelaziz Sefiani
BACKGROUND: Scleroderma is a multisystem disease, characterized by fibrosis of skin and internal organs, immune dysregulation, and vasculopathy. The etiology of the disease remains unknown, but it is likely multifactorial. However, the genetic basis for this condition is defined by multiple genes that have only modest effect on disease susceptibility. METHODS: Three Moroccan siblings, born from non-consanguineous Moroccan healthy parents were referred for genetic evaluation of familial scleroderma...
September 26, 2017: Pediatric Rheumatology Online Journal
https://www.readbyqxmd.com/read/28936784/cryo-em-structures-of-the-mammalian-endo-lysosomal-trpml1-channel-elucidate-the-combined-regulation-mechanism
#16
Sensen Zhang, Ningning Li, Wenwen Zeng, Ning Gao, Maojun Yang
TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca2+ permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols...
November 2017: Protein & Cell
https://www.readbyqxmd.com/read/28918368/gnptab-missense-mutations-cause-loss-of-glcnac-1-phosphotransferase-activity-in-mucolipidosis-type-ii-through-distinct-mechanisms
#17
Nataniel Floriano Ludwig, Renata Voltolini Velho, Fernanda Sperb-Ludwig, Angelina Xavier Acosta, Erlane Marques Ribeiro, Chong A Kim, Dafne Dain Gandelman Horovitz, Raquel Boy, Maria Juliana Rodovalho-Doriqui, Charles Marques Lourenço, Emerson Santana Santos, Thomas Braulke, Sandra Pohl, Ida Vanessa D Schwartz
Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the α⁄β-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p...
November 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28693924/site-1-protease-and-lysosomal-homeostasis
#18
REVIEW
Renata Voltolini Velho, Raffaella De Pace, Sarah Klünder, Giorgia Di Lorenzo, Michaela Schweizer, Thomas Braulke, Sandra Pohl
The Golgi-resident site-1 protease (S1P) is a key regulator of cholesterol homeostasis and ER stress responses by converting latent transcription factors sterol regulatory element binding proteins (SREPBs) and activating transcription factor 6 (ATF6), as well as viral glycoproteins to their active forms. S1P is also essential for lysosome biogenesis via proteolytic activation of the hexameric GlcNAc-1-phosphotransferase complex required for modification of newly synthesized lysosomal enzymes with the lysosomal targeting signal, mannose 6-phosphate...
November 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28689729/trpml1-the-ca-2-retaker-of-the-lysosome
#19
REVIEW
Simone Di Paola, Anna Scotto-Rosato, Diego Luis Medina
Efficient functioning of lysosome is necessary to ensure the correct performance of a variety of intracellular processes such as degradation of cargoes coming from the endocytic and autophagic pathways, recycling of organelles, and signaling mechanisms involved in cellular adaptation to nutrient availability. Mutations in lysosomal genes lead to more than 50 lysosomal storage disorders (LSDs). Among them, mutations in the gene encoding TRPML1 (MCOLN1) cause Mucolipidosis type IV (MLIV), a recessive LSD characterized by neurodegeneration, psychomotor retardation, ophthalmologic defects and achlorhydria...
January 2018: Cell Calcium
https://www.readbyqxmd.com/read/28610891/n-butyldeoxynojirimycin-delays-motor-deficits-cerebellar-microgliosis-and-purkinje-cell-loss-in-a-mouse-model-of-mucolipidosis-type-iv
#20
Lauren C Boudewyn, Jakub Sikora, Ladislav Kuchar, Jana Ledvinova, Yulia Grishchuk, Shirley L Wang, Kostantin Dobrenis, Steven U Walkley
Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss...
September 2017: Neurobiology of Disease
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