Juvenile Mucopolysaccharidosis plus disease caused by a missense mutation inVPS33A DOI Creative Commons
Elena Pavlova, Dorit Lev, Marina Michelson

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 30, 2022

ABSTRACT Background A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components the membrane-tethering protein complexes, HOPS CORVET. Methods Whole Exome Sequencing identified a novel VPS33A mutation patient suffering from variant form mucopolysaccharidosis. Electron confocal microscopy, immunoblotting, glycosphingolipid experiments were undertaken investigate effects mutant patient-derived skin fibroblasts. Results We describe an attenuated juvenile VPS33A-related syndrome - plus man who homozygous for hitherto unknown missense (NM_022916.4: c.599 G>C; R200P) conserved region gene. Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates hyaluronic acid. showed decreased abundance derived fibroblasts provided evidence that R200P leads destabilisation proteasomal degradation. As infantile plus, compartment also expanded – phenomenon accompanied endolysosomal acidification trafficking. Experimental treatment patient’s cultured with proteasome inhibitor, bortezomib, or exposure inhibitor glucosylceramide synthesis, eliglustat, improved Conclusion To our knowledge this first report insufficiency characterised appreciable residual endosomal-lysosomal milder than infants. Our findings expand proof concept redeploying clinically approved drugs therapeutic exploitation patients as well forms disease.

Language: Английский

HOPS, CORVET and newly-identified Hybrid tethering complexes contribute differentially towards multiple modes of endocytosis DOI Creative Commons
Seigo Terawaki,

Filipp Vasilev,

Takahito Moriwaki

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 31, 2023

Abstract Vesicular transport driven by membrane trafficking systems conserved in eukaryotes is critical to cellular functionality and homeostasis. It known that homotypic fusion vacuole protein sorting (HOPS) class C core endosomal tethering (CORVET) interact with Rab-GTPases SNARE proteins regulate vesicle transport, fusion, maturation autophagy endocytosis pathways. In this study, we identified two novel “Hybrid” complexes mammalian cells which one of the subunits HOPS or CORVET replaced subunit from other. Substrates taken up receptor-mediated pinocytosis were transported distinctive pathways, newly hybrid contributed presence HOPS, whereas was exclusively dependent on HOPS. Our study provides new insights into molecular mechanisms endocytic pathway function vacuolar sorting-associated (VPS) family.

Language: Английский

Citations

9
Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS) DOI Open Access
Viktoriia Sofronova,

L. Gotovtseva,

Anastasia Danilova

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(8), P. 1581 - 1581

Published: Aug. 3, 2023

Mucopolysaccharidosis-plus syndrome (MPSPS) is an autosomal-recessive disorder caused by c.1492C>T (p.R498W) in the VPS33A gene. MPSPS a severe that causes short lifespan patients. Currently, there no specific treatment for The Yakut population more prone to this disease than others. Diagnosing relies on clinical manifestations, and genetic testing (GT) used confirm diagnosis. In research, we examined two pregnancy cases, one of which involved prenatal diagnosis MPSPS. Notably, neither pregnant woman had known family history disorder. During their pregnancies, both women underwent ultrasonography, revealed increased prenasal thickness during second trimester. first case, ultrasonography indicated trimester, but definitive was not made at time. patient eventually diagnosed with 11 months age. On contrary, GT uncovered parents were carriers Consequently, placental biopsy performed, leading early This study emphasizes importance findings Combining can be valuable approach confirming stage, allowing appropriate planning delivery methods medical care. Ultimately, comprehensive significantly enhance quality life affected patients parents.

Language: Английский

Citations

4
Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A DOI Open Access
Elena Pavlova, Dorit Lev, Marina Michelson

et al.

Human Mutation, Journal Year: 2022, Volume and Issue: 43(12), P. 2265 - 2278

Published: Sept. 25, 2022

A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components the membrane-tethering protein complexes, HOPS, CORVET. Whole exome sequencing identified a novel VPS33A mutation patient suffering from variant form mucopolysaccharidosis. Electron confocal microscopy, immunoblotting, glycosphingolipid experiments were undertaken investigate effects mutant patient-derived skin fibroblasts. We describe an attenuated juvenile VPS33A-related syndrome-mucopolysaccharidosis plus man who homozygous for hitherto unknown missense (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) conserved region gene. Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, hyaluronic acid. showed decreased abundance derived fibroblasts provided evidence that p.Arg200Pro leads destablization proteasomal degradation. As infantile plus, compartment also expanded-a phenomenon accompanied endolysosomal acidification trafficking. Experimental treatment patient's cultured with proteasome inhibitor, bortezomib, or exposure inhibitor glucosylceramide synthesis, eliglustat, improved To our knowledge this first report insufficiency characterized appreciable residual endosomal-lysosomal milder than infants. Our findings expand proof concept redeploying clinically approved drugs therapeutic exploitation patients as well forms disease.

Language: Английский

Citations

7
Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease? DOI Open Access

Zuzanna Cyske,

Lidia Gaffke, Karolina Pierzynowska

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9570 - 9570

Published: Sept. 4, 2024

Several years ago, dozens of cases were described in patients with symptoms very similar to mucopolysaccharidosis (MPS). This new disease entity was as mucopolysaccharidosis-plus syndrome (MPSPS). The name the indicates that addition typical conventional MPS, develop other features such congenital heart defects and kidney hematopoietic system disorders. are highly advanced, usually do not survive past second year life. MPSPS is inherited an autosomal recessive manner caused by a homozygous-specific mutation gene encoding VPS33A protein. To date, it has been 41 patients. Patients exhibited excessive excretion glycosaminoglycans (GAGs) urine exceptionally high levels heparan sulfate plasma, but accumulation substrates decrease activity any lysosomal enzymes. Here, we discuss pathomechanisms MPSPS, comparing them those MPS. Moreover, asked question whether should be classified type MPS or separate disease, contrary ‘classical’ types, despite GAG accumulation, no enzymes responsible for degradation these compounds could detected MPSPS. molecular mechanism appearance suggested on basis results available literature.

Language: Английский

Citations

1
Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients DOI Open Access
Patryk Lipiński, Krzysztof Szczałuba, Piotr Buda

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11424 - 11424

Published: Sept. 28, 2022

Eleven patients from Yakutia with a new lysosomal disease assumed then as mucopolysaccharidosis-plus syndrome (MPS-PS) were reported by Gurinova et al. in 2014. Up to now, total number of 39 have been reported; all them, the c.1492C>T (p.Arg498Trp) variant VPS33A gene was detected. Here, we describe first Polish MPS-PS patient novel homozygous c.599G>C (p.Arg200Pro) presenting over 12 years follow-up some clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal growth, visceral obesity. Functional analyses revealed slight presence chondroitin sulphate (only) urine glycosaminoglycan electrophoresis, sialooligosaccharides thin-layer chromatography, results enzymes activity lysosphingolipids concentration dried blood spot. The comparison other described cases also provided. presented description natural history our may broaden spectrum phenotypes this disease.

Language: Английский

Citations

5
Screening core genes for minimal change disease based on bioinformatics and machine learning approaches DOI

Dingfan Hao,

Xiuting Yang,

Zexuan Li

et al.

International Urology and Nephrology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 9, 2024

Language: Английский

Citations

0
Urine proteome uncover common mechanism between mucopolysaccharidosis type I and II DOI Creative Commons
Xiaozhou Yuan,

Donghao Jia,

gefan Wan

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 14, 2023

Abstract Mucopolysaccharidosis (MPS) type I and II are two types of rare lysosomal storage diseases, which lead to the accumulation glycosaminoglycans due lack enzyme alpha-L-iduronidase (IDUA) iduronate 2-sulfatase (IDS) respectively. There some similar pathogenic mechanisms clinical phenotypes but also specific minute manifestations between these subtypes. To better understand similarities in pathogenesis symptoms diseases mechanism differential symptoms, we used TMT technology analyze protein profiles urine MPS patients. We detected proteins compared with control group separately. After that, focused on 227 differentially expressed (DEPs) showed consistent changes both II. Parallel reaction monitoring (PRM) analysis verified that up-regulated HEXB down-regulated HBA1 significant difference In addition, found 391 DEPs by comparative proteomes DHRS2 contributed subtypes PRM verification. Therefore, our study demonstrates value multi-sample proteomics combined exploring differences functional II, provides a new idea for characteristics exploration common treatment options.

Language: Английский

Citations

0
Juvenile Mucopolysaccharidosis plus disease caused by a missense mutation inVPS33A DOI Creative Commons
Elena Pavlova, Dorit Lev, Marina Michelson

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 30, 2022

ABSTRACT Background A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components the membrane-tethering protein complexes, HOPS CORVET. Methods Whole Exome Sequencing identified a novel VPS33A mutation patient suffering from variant form mucopolysaccharidosis. Electron confocal microscopy, immunoblotting, glycosphingolipid experiments were undertaken investigate effects mutant patient-derived skin fibroblasts. Results We describe an attenuated juvenile VPS33A-related syndrome - plus man who homozygous for hitherto unknown missense (NM_022916.4: c.599 G>C; R200P) conserved region gene. Urinary glycosaminoglycan analysis revealed increased heparan, dermatan sulphates hyaluronic acid. showed decreased abundance derived fibroblasts provided evidence that R200P leads destabilisation proteasomal degradation. As infantile plus, compartment also expanded – phenomenon accompanied endolysosomal acidification trafficking. Experimental treatment patient’s cultured with proteasome inhibitor, bortezomib, or exposure inhibitor glucosylceramide synthesis, eliglustat, improved Conclusion To our knowledge this first report insufficiency characterised appreciable residual endosomal-lysosomal milder than infants. Our findings expand proof concept redeploying clinically approved drugs therapeutic exploitation patients as well forms disease.

Language: Английский

Citations

0