keyword

Lysosomal storage diseases

keyword
https://read.qxmd.com/read/32220096/disease-causing-missense-mutations-within-the-n-terminal-transmembrane-domain-of-glcnac-1-phosphotransferase-impair-endoplasmic-reticulum-translocation-or-golgi-retention
#1
Wang-Sik Lee, Benjamin C Jennings, Balraj Doray, Stuart Kornfeld
Transport of newly synthesized lysosomal enzymes to the lysosome requires tagging of these enzymes with the mannose 6-phosphate moiety by UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase), encoded by two genes, GNPTAB and GNPTG. GNPTAB encodes the α and β subunits, which are initially synthesized as a single precursor that is cleaved by Site-1 protease in the Golgi. Mutations in this gene cause the lysosomal storage disorders mucolipidosis II (MLII) and mucolipidosis III αβ (MLIII αβ)...
March 27, 2020: Human Mutation
https://read.qxmd.com/read/32220057/long-term-observation-of-a-japanese-mucolipidosis-iv-patient-with-a-novel-homozygous-p-f313del-variant-of-mcoln1
#2
Takaaki Hayashi, Katsuhiro Hosono, Akiko Kubo, Kentaro Kurata, Satoshi Katagiri, Kei Mizobuchi, Minehiro Kurai, Norihito Mamiya, Mineo Kondo, Toshiaki Tachibana, Hirotomo Saitsu, Tsutomu Ogata, Tadashi Nakano, Yoshihiro Hotta
Mucolipidosis type IV (MLIV) is an autosomal recessively inherited lysosomal storage disorder characterized by progressive psychomotor delay and retinal degeneration that is associated with biallelic variants in the MCOLN1 gene. The gene, which is expressed in late endosomes and lysosomes of various tissue cells, encodes the transient receptor potential channel mucolipin 1 consisting of six transmembrane domains. Here, we described 14-year follow-up observation of a 4-year-old Japanese male MLIV patient with a novel homozygous in-frame deletion variant p...
March 27, 2020: American Journal of Medical Genetics. Part A
https://read.qxmd.com/read/32218723/protein-aggregation-and-dysfunction-of-autophagy-lysosomal-pathway-a-vicious-cycle-in-lysosomal-storage-diseases
#3
Antonio Monaco, Alessandro Fraldi
Many neurodegenerative conditions are characterized by the deposition of protein aggregates (mainly amyloid-like) in the central nervous system (CNS). In post-mitotic CNS cells protein aggregation causes cytotoxicity by interfering with various cellular functions. Mutations in different genes may directly cause protein aggregation. However, genetic factors together with aging may contribute to the onset of protein aggregation also by affecting cellular degradative functions, in particular the autophagy-lysosomal pathway (ALP)...
2020: Frontiers in Molecular Neuroscience
https://read.qxmd.com/read/32214050/the-respiratory-phenotype-of-pompe-disease-mouse-models
#4
REVIEW
Anna F Fusco, Angela L McCall, Justin S Dhindsa, Lucy Zheng, Aidan Bailey, Amanda F Kahn, Mai K ElMallah
Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models...
March 24, 2020: International Journal of Molecular Sciences
https://read.qxmd.com/read/32204338/different-trafficking-phenotypes-of-niemann-pick-c1-gene-mutations-correlate-with-various-alterations-in-lipid-storage-membrane-composition-and-miglustat-amenability
#5
Graham Brogden, Hadeel Shammas, Friederike Walters, Katia Maalouf, Anibh M Das, Hassan Y Naim, Sandra Rizk
Niemann-Pick Type C (NPC) is an autosomal recessive lysosomal storage disease leading to progressive neurodegeneration. Mutations in the NPC1 gene, which accounts for 95% of the cases, lead to a defect in intra-lysosomal trafficking of cholesterol and an accumulation of storage material including cholesterol and sphingolipids in the endo-lysosomal system. Symptoms are progressive neurological and visceral deterioration, with variable onset and severity of the disease. This study investigates the influence of two different NPC1 mutations on the biochemical phenotype in fibroblasts isolated from NPC patients in comparison to healthy, wild type (WT) cells...
March 19, 2020: International Journal of Molecular Sciences
https://read.qxmd.com/read/32201884/variants-in-saposin-d-domain-of-prosaposin-gene-linked-to-parkinson-s-disease
#6
Yutaka Oji, Taku Hatano, Shin-Ichi Ueno, Manabu Funayama, Kei-Ichi Ishikawa, Ayami Okuzumi, Sachiko Noda, Shigeto Sato, Wataru Satake, Tatsushi Toda, Yuanzhe Li, Tomoko Hino-Takai, Soichiro Kakuta, Taiji Tsunemi, Hiroyo Yoshino, Kenya Nishioka, Tatsuya Hattori, Yasuaki Mizutani, Tatsuro Mutoh, Fusako Yokochi, Yuta Ichinose, Kishin Koh, Kazumasa Shindo, Yoshihisa Takiyama, Tsuyoshi Hamaguchi, Masahito Yamada, Matthew J Farrer, Yasuo Uchiyama, Wado Akamatsu, Yih-Ru Wu, Junko Matsuda, Nobutaka Hattori
Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes...
March 23, 2020: Brain
https://read.qxmd.com/read/32201668/a-basic-understanding-of-mucopolysaccharidosis-incidence-clinical-features-diagnosis-and-management
#7
REVIEW
Jing Zhou, Jing Lin, Wing Ting Leung, Ling Wang
Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases (LSD) with multi-organic and severe symptoms. MPS occur worldwide in various forms though have relative a low incidence. The prevalent type of MPS varies among different continents, indicating that it may be associated with region and ethnic background. Undegraded glycosaminoglycans (GAGs) induced by deficiency of enzymes are the primary cause of MPS. Clinical features differ depending on the specific enzyme deficiency including coarse facial features, cognitive retardation, hepatosplenomegaly, hernias, kyphoscoliosis, corneal clouding, etc...
February 2020: Intractable & Rare Diseases Research
https://read.qxmd.com/read/32200326/glucocerebrosidase-gcase-activity-modulation-by-2-alkyl-trihydroxypiperidines-inhibition-and-pharmacological-chaperoning
#8
F Clemente, C Matassini, C Faggi, S Giachetti, C Cresti, A Morrone, P Paoli, A Goti, M Martínez-Bailén, F Cardona
The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids...
March 9, 2020: Bioorganic Chemistry
https://read.qxmd.com/read/32198894/treatment-of-fabry-disease-with-migalastat-outcome-from-a-prospective-observational-multicenter-study-famous
#9
Malte Lenders, Peter Nordbeck, Christine Kurschat, Nesrin Karabul, Jessica Kaufeld, Julia B Hennermann, Monica Patten, Markus Cybulla, Jonas Müntze, Nurcan Üçeyler, Dan Liu, Anibh M Das, Claudia Sommer, Christian Pogoda, Stefanie Reiermann, Thomas Duning, Jens Gaedeke, Katharina Stumpfe, Daniela Blaschke, Stefan-Martin Brand, W Alexander Mann, Christoph Kampmann, Nicole Muschol, Sima Canaan-Kühl, Eva Brand
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) leading to intracellular accumulation of globotriaosylceramide (Gb3). Patients with amenable mutations can be treated with migalastat, a recently approved oral pharmacologic chaperone to increase endogenous α-Gal A activity. We assessed safety along with cardiovascular, renal, and patient-reported outcomes and disease biomarkers in a prospective observational multicenter study after 12 months of migalastat treatment under "real world" conditions...
March 21, 2020: Clinical Pharmacology and Therapeutics
https://read.qxmd.com/read/32198276/use-of-human-induced-pluripotent-stem-cells-and-kidney-organoids-to-develop-a-cysteamine-mtor-inhibition-combination-therapy-for-cystinosis
#10
Jennifer A Hollywood, Aneta Przepiorski, Randall F D'Souza, Sreevalsan Sreebhavan, Ernst J Wolvetang, Patrick T Harrison, Alan J Davidson, Teresa M Holm
BACKGROUND: Mutations in CTNS -a gene encoding the cystine transporter cystinosin-cause the rare, autosomal, recessive, lysosomal-storage disease cystinosis. Research has also implicated cystinosin in modulating the mTORC1 pathway, which serves as a core regulator of cellular metabolism, proliferation, survival, and autophagy. In its severest form, cystinosis is characterized by cystine accumulation, renal proximal tubule dysfunction, and kidney failure. Because treatment with the cystine-depleting drug cysteamine only slows disease progression, there is an urgent need for better treatments...
March 20, 2020: Journal of the American Society of Nephrology: JASN
https://read.qxmd.com/read/32192868/vestronidase-alfa-recombinant-human-%C3%AE-glucuronidase-as-an-enzyme-replacement-therapy-for-mps-vii
#11
Jaclyn Cadaoas, Gabrielle Boyle, Steven Jungles, Sean Cullen, Michel Vellard, Jeffrey H Grubb, Agnieszka Jurecka, William Sly, Emil Kakkis
Mucopolysaccharidosis VII (MPS VII) is a rare lysosomal storage disease characterized by a deficiency in the enzyme β-glucuronidase that has previously been successfully treated in a mouse model with enzyme replacement therapy. Here, we present the generation of a novel, highly sialylated version of recombinant human β-glucuronidase (rhGUS), vestronidase alfa, that has high uptake, resulting in an improved enzyme replacement therapy for the treatment of patients with MPS VII. In vitro, vestronidase alfa has 10-fold more sialic acid per mole of rhGUS monomer than a prior rhGUS version (referred to as GUS 43/44) and demonstrated very high affinity at ~1 nM half maximal uptake in human MPS VII fibroblasts...
March 6, 2020: Molecular Genetics and Metabolism
https://read.qxmd.com/read/32189245/clinical-course-and-pathological-findings-of-two-late-onset-fabry-hemizygous-patients-including-mulberry-cell-counts-after-enzyme-replacement-therapy
#12
Homare Shimohata, Marina Yamashita, Kentaro Ohgi, Hiroshi Maruyama, Mamiko Takayasu, Kouichi Hirayama, Masaki Kobayashi
Fabry disease is an X-linked inherited lysosomal storage disorder caused by a deficiency of α-galactosidase A activity, resulting in the intracellular accumulation of globotriaosylceramide and related glycosphingolipids. The phenotypes of Fabry disease in both males and females are grouped into two categories: the classical type and the late-onset type. The classical type shows general symptoms including angiokeratoma(s), acroparesthesia, hypohidrosis, corneal opacity, and gastrointestinal symptoms from an early age...
March 18, 2020: CEN Case Reports
https://read.qxmd.com/read/32189222/impact-of-gene-therapy-for-canine-monogenic-diseases-on-the-progress-of-preclinical-studies
#13
REVIEW
Marek Switonski
Rapid progress in knowledge of the organization of the dog genome has facilitated the identification of the mutations responsible for numerous monogenic diseases, which usually present a breed-specific distribution. The majority of these diseases have clinical and molecular counterparts in humans. The affected dogs have thus become valuable models for preclinical studies of gene therapy for problems such as eye diseases, immunodeficiency, lysosomal storage diseases, hemophilia, and muscular dystrophy. Successful gene therapies in dogs have significantly contributed to decisions to run clinical trials for several human diseases, such as Leber's congenital amaurosis 2-LCA2 (caused by a mutation of RPE65), X-linked retinitis pigmentosa-XLRP (caused by mutation RPGR), and achromatopsia (caused by mutation of CNGB3)...
March 18, 2020: Journal of Applied Genetics
https://read.qxmd.com/read/32188102/validation-of-liquid-chromatography-tandem-mass-spectrometry-based-5-plex-assay-for-mucopolysaccharidoses
#14
Tsubasa Oguni, Shunji Tomatsu, Misa Tanaka, Kenji Orii, Toshiyuki Fukao, Jun Watanabe, Seiji Fukuda, Yoshitomo Notsu, Dung Chi Vu, Thi Bich Ngoc Can, Atsushi Nagai, Seiji Yamaguchi, Takeshi Taketani, Michael H Gelb, Hironori Kobayashi
Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for simultaneous preparation and better measurement of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and 23 patients with MPS...
March 16, 2020: International Journal of Molecular Sciences
https://read.qxmd.com/read/32186243/molecular-dynamics-simulations-to-decipher-the-structural-and-functional-consequences-of-pathogenic-missense-mutations-in-the-galactosylceramidase-galc-protein-causing-krabbe-s-disease
#15
D Thirumal Kumar, Nikita Jain, S Udhaya Kumar, Prangya Paramita Jena, Siva Ramamoorthy, C George Priya Doss, Hatem Zayed
Krabbe disease (KD), also known as globoid cell leukodystrophy disease, is an autosomal recessive lysosomal storage genetic disorder, which is caused by the deficiecncy of galactocerebrosidase (GALC) coding gene ( GALC ). This sudy aimed to use an extensive computational pipelines in understanding the missense mutations in GALC. We retrieved 176 mutations from the public databases and subjected them to pathogenicity, stability, and conservation analysis. The PredictSNP, iStable, and ConSurf prediction tools predicted 45, 95, and 47 mutations to be deleterious, destabilizing, and highly conserved, respectively...
March 18, 2020: Journal of Biomolecular Structure & Dynamics
https://read.qxmd.com/read/32184778/trpml-cation-channels-in-inflammation-and-immunity
#16
REVIEW
Barbara Spix, Yu-Kai Chao, Carla Abrahamian, Cheng-Chang Chen, Christian Grimm
Background: In 1883, Ilya Mechnikov discovered phagocytes and established the concept of phagocytosis by macrophages. In 1908, he was awarded the Nobel Prize in Physiology/Medicine for his findings, which laid the foundations for today's understanding of the innate immune response. Only in the 1960s, Max Cooper and Robert Good significantly advanced our understanding of the immune system by demonstrating that B- and T-cells cooperate to regulate the adaptive immune response. Both, innate and adaptive immune response are essential to effectively protect the individual against infectious agents, such as viruses, bacterial or insect toxins, or allergens...
2020: Frontiers in Immunology
https://read.qxmd.com/read/32183018/elevated-lysogb3-concentration-in-the-neuronopathic-forms-of-mucopolysaccharidoses
#17
Galina Baydakova, Alex Ilyushkina, Lidia Gaffke, Karolina Pierzynowska, Igor Bychkov, Agnieszka Ługowska, Grzegorz Wegrzyn, Anna Tylki-Szymanska, Ekaterina Zakharova
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease-Fabry disease...
March 13, 2020: Diagnostics
https://read.qxmd.com/read/32182893/glucocerebrosidase-functions-in-and-beyond-the-lysosome
#18
REVIEW
Daphne E C Boer, Jeroen van Smeden, Joke A Bouwstra, Johannes M F G Aerts
Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes...
March 9, 2020: Journal of Clinical Medicine
https://read.qxmd.com/read/32182687/hip-morphology-in-mucolipidosis-type-ii
#19
Luise Sophie Ammer, Esmeralda Oussoren, Nicole Maria Muschol, Sandra Pohl, Maria Estela Rubio-Gozalbo, René Santer, Ralf Stuecker, Eik Vettorazzi, Sandra Rafaela Breyer
Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies in MLII by systematic evaluation of plain radiographs, ultrasounds and magnetic resonance imaging (MRI). An international two-centered study was performed by retrospective chart review. All MLII patients with at least one pelvic radiograph were included...
March 8, 2020: Journal of Clinical Medicine
https://read.qxmd.com/read/32176488/lead-optimization-of-benzoxazolone-carboxamides-as-orally-bioavailable-and-cns-penetrant-acid-ceramidase-inhibitors
#20
Simona Di Martino, Piero Tardia, Vincenzo Cilibrasi, Samantha Caputo, Marco Mazzonna, Debora Russo, Ilaria Penna, Natalia Realini, Natasha Margaroli, Marco Migliore, Daniela Pizzirani, Giuliana Ottonello, Sine Mandrup Bertozzi, Andrea Armirotti, Duc Nguyen, Ying Sun, Ernesto Bongarzone, Peter Lansbury, Min Liu, Renato T Skerlj, Rita Scarpelli
Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL- related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m , where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases...
March 16, 2020: Journal of Medicinal Chemistry
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