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      Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency


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          Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described.


          In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis.


          The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS.


          Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.

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          GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.

          Here, we describe an overview and update on GeneMatcher (http://www.genematcher.org), a freely accessible Web-based tool developed as part of the Baylor-Hopkins Center for Mendelian Genomics. We created GeneMatcher with the goal of identifying additional individuals with rare phenotypes who had variants in the same candidate disease gene. We also wanted to facilitate connections to basic scientists working on orthologous genes in model systems with the goal of connecting their work to human Mendelian phenotypes. Meeting these goals will enhance the identification of novel Mendelian genes. Launched in September, 2013, GeneMatcher now has 2,178 candidate genes from 486 submitters spread across 38 countries entered in the database (June 1, 2015). GeneMatcher is also part of the Matchmaker Exchange (http://matchmakerexchange.org/) with an Application Programing Interface enabling submitters to query other databases of genetic variants and phenotypes without having to create accounts and data entries in multiple systems.
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            Nosology and classification of genetic skeletal disorders: 2019 revision

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              Mucopolysaccharidoses and the eye.

              The mucopolysaccharidoses (MPSs) are a group of disorders caused by inherited defects in lysosomal enzymes resulting in widespread intra- and extra-cellular accumulation of glycosaminoglycans. They have been subdivided according to enzyme defect and systemic manifestations and include MPS IH (Hurler), MPS IS (Scheie), MPS IH/S (Hurler/Sheie), MPS II (Hunter), MPS III (Sanfilippo), MPS IV (Morquio), MPS VI (Maroteaux-Lamy), MPS VII (Sly) and MPS IX (Natowicz). The mucopolysaccharidoses have a spectrum of systemic manifestations, including airway and respiratory compromise, skeletal deformities, intellectual and neurological impairment, cardiac abnormalities, and gastrointestinal problems. Ocular manifestations are common in the mucopolysaccharidoses and may result in significant visual impairment. Corneal opacification of varying severity is frequently seen, as well as retinopathy, optic nerve swelling and atrophy, ocular hypertension, and glaucoma. New treatment modalities for the systemic manifestations of the mucopolysaccharidoses include bone marrow transplant and enzyme replacement therapy, and have resulted in an improved prognosis in many cases. This article reviews the systemic and ocular manifestations of the mucopolysaccharidoses, as well as new treatment options, and discusses the ophthalmic management of mucopolysaccharidosis patients.

                Author and article information

                J Med Genet
                J Med Genet
                Journal of Medical Genetics
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                October 2022
                16 December 2021
                : 59
                : 10
                : 957-964
                [1 ] departmentDiagnostic and Research Center for Molecular BioMedicine , Medical University of Graz , Graz, Austria
                [2 ] departmentDepartment of Medical Genetics , Kasturba Medical College, Manipal, Manipal Academy of Higher Education , Manipal, India
                [3 ] departmentComplex Carbohydrate Research Center , University of Georgia , Athens, Georgia, USA
                [4 ] departmentDepartment of Chemistry , University of Georgia , Athens, Georgia, USA
                [5 ] departmentDepartment of Chemistry, Biochemistry , Bielefeld University , Bielefeld, Germany
                [6 ] departmentFaculty of Chemistry, Industrial Organic Chemistry and Biotechnology - Mass Spectrometry , Bielefeld University , Bielefeld, Germany
                [7 ] departmentLaboratory Genetic Metabolic Disease, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Core Facility Metabolomics, Emma Children’s Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands , Amsterdam UMC Locatie Meibergdreef , Amsterdam, North Holland, The Netherlands
                [8 ] departmentInstitute of Medical Chemistry , Medical University of Vienna , Vienna, Austria
                [9 ] departmentDepartment of Ophthalmology , Medical University of Graz , Graz, Austria
                [10 ] departmentDepartment of Pediatrics and Adolescent Medicine; Division of Pediatric Cardiology , Medical University of Graz , Graz, Austria
                [11 ] departmentDepartment of Orthopedics , Kasturba Medical College Manipal , Manipal, India
                [12 ] departmentPediatric Department , Speising Orthopaedic Hospital , Vienna, Austria
                [13 ] departmentDepartment of Pediatrics, Division of General Pediatrics , Medical University of Graz , Graz, Austria
                Author notes
                [Correspondence to ] Professor Barbara Plecko, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria; barbara.plecko@ 123456medunigraz.at ; Dr Katta M Girisha, Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India; girish.katta@ 123456manipal.edu

                AAK, KMG and BP are joint last authors.

                Author information
                © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                : 28 June 2021
                : 31 October 2021
                Funded by: Science and Engineering Research Board, Department of Science and Technology, Government of India;
                Award ID: SB/SO/HS/005/2014
                Biochemical Genetics
                Original research
                Custom metadata

                phenotype,human genetics,genetics,pediatrics,orthopedics
                phenotype, human genetics, genetics, pediatrics, orthopedics


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