{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:14:54Z","timestamp":1791976494466,"version":"4.4.0"},"reference-count":122,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Engineering Council of Canada","award":["RGPIN-2017-04953 (BT-R)"],"award-info":[{"award-number":["RGPIN-2017-04953 (BT-R)"]}]},{"name":"National Science and Engineering Council of Canada","award":["R50-CA211119"],"award-info":[{"award-number":["R50-CA211119"]}]},{"name":"National Institutes of Health","award":["RGPIN-2017-04953 (BT-R)"],"award-info":[{"award-number":["RGPIN-2017-04953 (BT-R)"]}]},{"name":"National Institutes of Health","award":["R50-CA211119"],"award-info":[{"award-number":["R50-CA211119"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hyaluronan (HA) is a large polysaccharide that is broadly distributed and highly abundant in the soft connective tissues and embryos of vertebrates. The constitutive turnover of HA is very high, estimated at 5 g per day in an average (70 kg) adult human, but HA turnover must also be tightly regulated in some processes. Six genes encoding homologues to bee venom hyaluronidase (HYAL1, HYAL2, HYAL3, HYAL4, HYAL6P\/HYALP1, SPAM1\/PH20), as well as genes encoding two unrelated G8-domain-containing proteins demonstrated to be involved in HA degradation (CEMIP\/KIAA1199, CEMIP2\/TMEM2), have been identified in humans. Of these, only deficiencies in HYAL1, HYAL2, HYAL3 and CEMIP have been identified as the cause or putative cause of human genetic disorders. The phenotypes of these disorders have been vital in determining the biological roles of these enzymes but there is much that is still not understood. Deficiencies in these HA-degrading proteins have been created in mice and\/or other model organisms where phenotypes could be analyzed and probed to expand our understanding of HA degradation and function. This review will describe what has been found in human and animal models of hyaluronidase deficiency and discuss how this has advanced our understanding of HA\u2019s role in health and disease.<\/jats:p>","DOI":"10.3390\/cells13141203","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T08:48:29Z","timestamp":1721206109000},"page":"1203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Genetic Deficiencies of Hyaluronan Degradation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-7912","authenticated-orcid":false,"given":"Stephen P.","family":"Fink","sequence":"first","affiliation":[{"name":"Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-6779","authenticated-orcid":false,"given":"Barbara","family":"Triggs-Raine","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"},{"name":"Children\u2019s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ricard-Blum, S., Vives, R.R., Schaefer, L., Gotte, M., Merline, R., Passi, A., Heldin, P., Magalhaes, A., Reis, C.A., and Skandalis, S.S. (2024). A biological guide to glycosaminoglycans: Current perspectives and pending questions. FEBS J.","DOI":"10.1111\/febs.17107"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1080\/15216540214929","article-title":"Mammalian hyaluronan synthases","volume":"54","author":"Itano","year":"2002","journal-title":"IUBMB Life"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/s41586-022-04534-2","article-title":"Structure, substrate recognition and initiation of hyaluronan synthase","volume":"604","author":"Maloney","year":"2022","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1046\/j.1365-2796.1997.00170.x","article-title":"Hyaluronan: Its nature, distribution, functions and turnover","volume":"242","author":"Fraser","year":"1997","journal-title":"J. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1432-0436.1993.tb01591.x","article-title":"Localization of hyaluronan in mouse embryos during implantation, gastrulation and organogenesis","volume":"54","author":"Fenderson","year":"1993","journal-title":"Differentiation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1096\/fasebj.6.7.1563592","article-title":"Hyaluronan","volume":"6","author":"Laurent","year":"1992","journal-title":"FASEB J."},{"key":"ref_7","first-page":"41","article-title":"Turnover and metabolism of hyaluronan","volume":"143","author":"Fraser","year":"1989","journal-title":"Ciba Found. Symp."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.matbio.2011.11.002","article-title":"A comprehensive model of hyaluronan turnover in the mouse","volume":"31","author":"Jadin","year":"2012","journal-title":"Matrix Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/bj2560153","article-title":"Uptake and degradation of hyaluronan in lymphatic tissue","volume":"256","author":"Fraser","year":"1988","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/BF00238296","article-title":"Tissue uptake of circulating hyaluronic acid. A whole body autoradiographic study","volume":"233","author":"Fraser","year":"1983","journal-title":"Cell Tissue Res."},{"key":"ref_11","first-page":"60","article-title":"Enzymic pathways of hyaluronan catabolism","volume":"143","author":"Roden","year":"1989","journal-title":"Ciba Found. Symp."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100874","DOI":"10.1016\/j.spen.2021.100874","article-title":"Update in the Mucopolysaccharidoses","volume":"37","author":"McBride","year":"2021","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1021\/cr050247k","article-title":"Hyaluronidases: Their genomics, structures, and mechanisms of action","volume":"106","author":"Stern","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16689","DOI":"10.1074\/jbc.M112.350447","article-title":"Hyaluronidase 1 and beta-hexosaminidase have redundant functions in hyaluronan and chondroitin sulfate degradation","volume":"287","author":"Gushulak","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1073\/pnas.90.8.3569","article-title":"Bee Venom Hyaluronidase Is Homologous to a Membrane-Protein of Mammalian Sperm","volume":"90","author":"Gmachl","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1006\/geno.1997.5158","article-title":"The hyaluronidase gene HYAL1 maps to chromosome 3p21.2-p21.3 in human and 9F1-F2 in mouse, a conserved candidate tumor suppressor locus","volume":"48","author":"Csoka","year":"1998","journal-title":"Genomics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1006\/geno.1999.5876","article-title":"Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31","volume":"60","author":"Csoka","year":"1999","journal-title":"Genomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6296","DOI":"10.1073\/pnas.96.11.6296","article-title":"Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX","volume":"96","author":"Salo","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22466","DOI":"10.1074\/jbc.273.35.22466","article-title":"HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity","volume":"273","author":"Lepperdinger","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23008","DOI":"10.1074\/jbc.M108991200","article-title":"Characterization of the murine hyaluronidase gene region reveals complex organization and cotranscription of Hyal1 with downstream genes, Fus2 and Hyal3","volume":"277","author":"Shuttleworth","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"18028","DOI":"10.1073\/pnas.0506825102","article-title":"Identification of a hyaluronidase, Hyal5, involved in penetration of mouse sperm through cumulus mass","volume":"102","author":"Kim","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/glycob\/cws218","article-title":"Hypotheses on the evolution of hyaluronan: A highly ironic acid","volume":"23","author":"Csoka","year":"2013","journal-title":"Glycobiology"},{"key":"ref_23","first-page":"6116","article-title":"The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: Identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium","volume":"60","author":"Lerman","year":"2000","journal-title":"Cancer Res."},{"key":"ref_24","first-page":"2715","article-title":"Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo","volume":"62","author":"Ji","year":"2002","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1093\/bfgp\/elm007","article-title":"Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease","volume":"6","author":"Angeloni","year":"2007","journal-title":"Brief. Funct. Genom. Proteomic"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5612","DOI":"10.1073\/pnas.1215432110","article-title":"KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization","volume":"110","author":"Yoshida","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7304","DOI":"10.1074\/jbc.M116.770149","article-title":"A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase","volume":"292","author":"Yamamoto","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.febslet.2013.11.017","article-title":"N-Terminal signal sequence is required for cellular trafficking and hyaluronan-depolymerization of KIAA1199","volume":"588","author":"Yoshida","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_29","first-page":"76","article-title":"Structure of the transmembrane protein 2 (TMEM2) ectodomain and its apparent lack of hyaluronidase activity","volume":"8","author":"Niu","year":"2023","journal-title":"Wellcome Open Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sato, S., Miyazaki, M., Fukuda, S., Mizutani, Y., Mizukami, Y., Higashiyama, S., and Inoue, S. (2023). Human TMEM2 is not a catalytic hyaluronidase, but a regulator of hyaluronan metabolism via HYBID (KIAA1199\/CEMIP) and HAS2 expression. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.104826"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.matbio.2018.03.020","article-title":"TMEM2: A missing link in hyaluronan catabolism identified?","volume":"78\u201379","author":"Yamaguchi","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1093\/bioinformatics\/btl123","article-title":"G8: A novel domain associated with polycystic kidney disease and non-syndromic hearing loss","volume":"22","author":"He","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1056\/NEJM199610033351405","article-title":"Clinical and biochemical manifestations of hyaluronidase deficiency","volume":"335","author":"Natowicz","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1007\/s10545-011-9343-3","article-title":"A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis","volume":"34","author":"Imundo","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/8904_2015_467","article-title":"Screening Mucopolysaccharidosis Type IX in Patients with Juvenile Idiopathic Arthritis","volume":"25","author":"Kiykim","year":"2016","journal-title":"JIMD Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1111\/j.1432-1033.1997.t01-1-00810.x","article-title":"In vitro mutagenesis of PH-20 hyaluronidase from human sperm","volume":"247","author":"Arming","year":"1997","journal-title":"Eur. J. Biochem.\/FEBS"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/S0969-2126(00)00511-6","article-title":"Crystal structure of hyaluronidase, a major allergen of bee venom","volume":"8","author":"Miglierini","year":"2000","journal-title":"Structure"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00249-016-1151-0","article-title":"In silico approach to explore the disruption in the molecular mechanism of human hyaluronidase 1 by mutant E268K that directs Natowicz syndrome","volume":"46","author":"Rajasekaran","year":"2017","journal-title":"Eur. Biophys. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/0003-9861(67)90037-9","article-title":"A comparison of serum and testicular hyaluronidase","volume":"121","author":"Plonska","year":"1967","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1006\/bbrc.1997.6773","article-title":"Purification, cloning, and expression of human plasma hyaluronidase","volume":"236","author":"Frost","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0014-5793(97)01309-4","article-title":"Purification and microsequencing of hyaluronidase isozymes from human urine","volume":"417","author":"Csoka","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1093\/glycob\/cwm003","article-title":"Recombinant human hyaluronidase Hyal-1:: Insect cells versus as expression system and identification of low molecular weight inhibitors","volume":"17","author":"Hofinger","year":"2007","journal-title":"Glycobiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.fob.2014.06.001","article-title":"N-glycosylation is required for secretion and enzymatic activity of human hyaluronidase1","volume":"4","author":"Goto","year":"2014","journal-title":"FEBS Open Bio"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6911","DOI":"10.1021\/bi700382g","article-title":"Structure of human hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis","volume":"46","author":"Chao","year":"2007","journal-title":"Biochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/(SICI)1096-8628(19961028)65:3<209::AID-AJMG7>3.0.CO;2-K","article-title":"Plasma hyaluronidase activity in mucolipidoses II and III: Marked differences from other lysosomal enzymes","volume":"65","author":"Natowicz","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/tra.12162","article-title":"Subcellular trafficking and activity of Hyal-1 and its processed forms in murine macrophages","volume":"15","author":"Puissant","year":"2014","journal-title":"Traffic"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1042\/BJ20100711","article-title":"Endocytosis of hyaluronidase-1 by the liver","volume":"430","author":"Gasingirwa","year":"2010","journal-title":"Biochem. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.bbrc.2014.03.070","article-title":"Mouse liver lysosomes contain enzymatically active processed forms of Hyal-1","volume":"446","author":"Boonen","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13144","DOI":"10.1074\/jbc.M115.647446","article-title":"Hyaluronidase Hyal1 Increases Tumor Cell Proliferation and Motility through Accelerated Vesicle Trafficking","volume":"290","author":"McAtee","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0945-053X(01)00172-X","article-title":"The six hyaluronidase-like genes in the human and mouse genomes","volume":"20","author":"Csoka","year":"2001","journal-title":"Matrix Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol. Cell. Proteom."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/gim.2015.147","article-title":"Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort","volume":"18","author":"Shaheen","year":"2016","journal-title":"Genet. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Muggenthaler, M.M., Chowdhury, B., Hasan, S.N., Cross, H.E., Mark, B., Harlalka, G.V., Patton, M.A., Ishida, M., Behr, E.R., and Sharma, S. (2017). Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006470"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.gim.2021.10.014","article-title":"Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency","volume":"24","author":"Fasham","year":"2022","journal-title":"Genet. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1006\/geno.1998.5472","article-title":"Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase","volume":"53","author":"Strobl","year":"1998","journal-title":"Genomics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.joca.2006.08.004","article-title":"Hyal2, where are you?","volume":"14","author":"Miller","year":"2006","journal-title":"Osteoarthr. Cartil. OARS Osteoarthr. Res. Soc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.bbrc.2011.06.125","article-title":"Hyal2 is a glycosylphosphatidylinositol-anchored, lipid raft-associated hyaluronidase","volume":"411","author":"Andre","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4443","DOI":"10.1073\/pnas.071572898","article-title":"Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation","volume":"98","author":"Rai","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0945-053X(01)00170-6","article-title":"Hyal2--less active, but more versatile?","volume":"20","author":"Lepperdinger","year":"2001","journal-title":"Matrix Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"26991","DOI":"10.1074\/jbc.M311838200","article-title":"CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion","volume":"279","author":"Bourguignon","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0945-053X(99)00045-1","article-title":"How does the hyaluronan scrap-yard operate?","volume":"18","author":"McCourt","year":"1999","journal-title":"Matrix Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"105R","DOI":"10.1093\/glycob\/cwg112","article-title":"Devising a pathway for hyaluronan catabolism: Are we there yet?","volume":"13","author":"Stern","year":"2003","journal-title":"Glycobiology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"110","DOI":"10.4331\/wjbc.v6.i3.110","article-title":"Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism","volume":"6","author":"Natowicz","year":"2015","journal-title":"World J. Biol. Chem."},{"key":"ref_64","unstructured":"Hascall, V., Sandy, J.D., and Handley, C.J. (1999). Regulation of proteoglycan metabolism in articular cartilage. Biology of the Synovial Joint, Harwood Academic Publishers. [Archer, C.W., Caterson, B.]."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"33495","DOI":"10.1074\/jbc.M109.044362","article-title":"Two novel functions of hyaluronidase-2 (Hyal2) are formation of the glycocalyx and control of CD44-ERM interactions","volume":"284","author":"Duterme","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1128\/JVI.79.1.79-86.2005","article-title":"Expression and characterization of a soluble, active form of the jaagsiekte sheep retrovirus receptor, Hyal2","volume":"79","author":"Vigdorovich","year":"2005","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.2353\/ajpath.2009.080831","article-title":"Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines","volume":"174","author":"Nigro","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1182\/blood-2014-07-590513","article-title":"Platelet hyaluronidase-2: An enzyme that translocates to the surface upon activation to function in extracellular matrix degradation","volume":"125","author":"Albeiroti","year":"2015","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e3589","DOI":"10.1002\/jgm.3589","article-title":"Identification of novel homozygous missense and deletion mutations manifesting oligospermia infertility in Kashmiri population","volume":"26","author":"Aslam","year":"2024","journal-title":"J. Gene Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/mrd.21217","article-title":"Acidic hyaluronidase activity is present in mouse sperm and is reduced in the absence of SPAM1: Evidence for a role for hyaluronidase 3 in mouse and human sperm","volume":"77","author":"Reese","year":"2010","journal-title":"Mol. Reprod. Dev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1007\/s10038-003-0079-2","article-title":"Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters\u2019 cells and the fibrocytes, as the cause of nonsyndromic hearing loss","volume":"48","author":"Abe","year":"2003","journal-title":"J. Hum. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1080\/00016480701785046","article-title":"The responsible genes in Japanese deafness patients and clinical application using Invader assay","volume":"128","author":"Usami","year":"2008","journal-title":"Acta Otolaryngol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"23761","DOI":"10.18632\/aging.103964","article-title":"Serum KIAA1199 is an advanced-stage prognostic biomarker and metastatic oncogene in cholangiocarcinoma","volume":"12","author":"Zhai","year":"2020","journal-title":"Aging"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Tiwari, A., Schneider, M., Fiorino, A., Haider, R., Okoniewski, M.J., Roschitzki, B., Uzozie, A., Menigatti, M., Jiricny, J., and Marra, G. (2013). Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069473"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"30500","DOI":"10.18632\/oncotarget.5921","article-title":"Induction of KIAA1199\/CEMIP is associated with colon cancer phenotype and poor patient survival","volume":"6","author":"Fink","year":"2015","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/s41556-019-0404-4","article-title":"Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis","volume":"21","author":"Rodrigues","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9280","DOI":"10.1073\/pnas.1525545113","article-title":"Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan","volume":"113","author":"Kuwabara","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.neuroscience.2008.03.018","article-title":"The localization of proteins encoded by CRYM, KIAA1199, UBA52, COL9A3, and COL9A1, genes highly expressed in the cochlea","volume":"154","author":"Usami","year":"2008","journal-title":"Neuroscience"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.canlet.2005.07.028","article-title":"Upregulation of the KIAA1199 gene is associated with cellular mortality","volume":"239","author":"Michishita","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7040","DOI":"10.18632\/oncotarget.2220","article-title":"KIAA1199 interacts with glycogen phosphorylase kinase beta-subunit (PHKB) to promote glycogen breakdown and cancer cell survival","volume":"5","author":"Terashima","year":"2014","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.3892\/or.2014.3038","article-title":"KIAA1199 and its biological role in human cancer and cancer cells (review)","volume":"31","author":"Zhang","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Domanegg, K., Sleeman, J.P., and Schmaus, A. (2022). CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer. Cancers, 14.","DOI":"10.3390\/cancers14205093"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1093\/jnci\/djt224","article-title":"Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration","volume":"105","author":"Evensen","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1158\/0008-5472.CAN-17-3149","article-title":"The Endosomal Protein CEMIP Links WNT Signaling to MEK1-ERK1\/2 Activation in Selumetinib-Resistant Intestinal Organoids","volume":"78","author":"Duong","year":"2018","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/bjc.2011.268","article-title":"Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells","volume":"105","author":"Maghnouj","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Yamada, S., and Mizumoto, S. (2022). Characterization of Hyaluronidase 4 Involved in the Catabolism of Chondroitin Sulfate. Molecules, 27.","DOI":"10.3390\/molecules27186103"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1093\/hmg\/ddn088","article-title":"A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis","volume":"17","author":"Martin","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"10142","DOI":"10.1038\/s41598-022-14473-7","article-title":"Hyaluronidase 1 deficiency decreases bone mineral density in mice","volume":"12","author":"Puissant","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1096\/fj.201500178R","article-title":"Respective roles of hyaluronidases 1 and 2 in endogenous hyaluronan turnover","volume":"30","author":"Bourguignon","year":"2016","journal-title":"FASEB J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.acthis.2014.11.007","article-title":"Hyaluronidase 1 and hyaluronidase 2 are required for renal hyaluronan turnover","volume":"117","author":"Colombaro","year":"2015","journal-title":"Acta Histochem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1038\/jid.2015.299","article-title":"Hyaluronidase-1 Is Mainly Functional in the Upper Granular Layer, Close to the Epidermal Barrier","volume":"135","author":"Malaisse","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1002\/jcp.22919","article-title":"Hyal-1 but not Hyal-3 deficiency has an impact on ovarian folliculogenesis and female fertility by altering the follistatin\/activin\/Smad3 pathway and the apoptotic process","volume":"227","author":"Edjekouane","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/ng1196-348","article-title":"Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis","volume":"14","author":"Sango","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1097\/00005072-199706000-00007","article-title":"Mice deficient in all forms of lysosomal beta-hexosaminidase show mucopolysaccharidosis-like pathology","volume":"56","author":"Suzuki","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4316","DOI":"10.1096\/fj.08-111997","article-title":"Skeletal and hematological anomalies in HYAL2-deficient mice: A second type of mucopolysaccharidosis IX?","volume":"22","author":"Jadin","year":"2008","journal-title":"FASEB J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1074\/jbc.M112.393629","article-title":"Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction","volume":"288","author":"Chowdhury","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00418-015-1373-8","article-title":"Hyaluronidase 2 (HYAL2) is expressed in endothelial cells, as well as some specialized epithelial cells, and is required for normal hyaluronan catabolism","volume":"145","author":"Chowdhury","year":"2016","journal-title":"Histochem. Cell Biol."},{"key":"ref_98","first-page":"1023","article-title":"Deficiency in mouse hyaluronidase 2: A new mechanism of chronic thrombotic microangiopathy","volume":"100","author":"Onclinx","year":"2015","journal-title":"Haematologica"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.ijcard.2016.02.072","article-title":"Hyaluronidase 2 deficiency is a molecular cause of cor triatriatum sinister in mice","volume":"209","author":"Chowdhury","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e001598","DOI":"10.1161\/CIRCGENETICS.116.001598","article-title":"Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure","volume":"10","author":"Chowdhury","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"7028","DOI":"10.1038\/s41598-017-07376-5","article-title":"Conditional knockdown of hyaluronidase 2 in articular cartilage stimulates osteoarthritic progression in a mice model","volume":"7","author":"Higuchi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.matbio.2008.07.006","article-title":"Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation","volume":"27","author":"Atmuri","year":"2008","journal-title":"Matrix Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1093\/glycob\/cwn006","article-title":"Mouse Hyal3 encodes a 45\u201356 kDa glycoprotein whose overexpression increases hyaluronidase 1 activity in cultured cells","volume":"18","author":"Hemming","year":"2008","journal-title":"Glycobiology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0945-053X(01)00171-8","article-title":"The dual functions of GPI-anchored PH-20: Hyaluronidase and intracellular signaling","volume":"20","author":"Cherr","year":"2001","journal-title":"Matrix Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"30310","DOI":"10.1074\/jbc.M204596200","article-title":"Mouse sperm lacking cell surface hyaluronidase PH-20 can pass through the layer of cumulus cells and fertilize the egg","volume":"277","author":"Baba","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"14440","DOI":"10.1096\/fj.201900889RRR","article-title":"SPAM1\/HYAL5 double deficiency in male mice leads to severe male subfertility caused by a cumulus-oocyte complex penetration defect","volume":"33","author":"Park","year":"2019","journal-title":"FASEB J."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Bang, H., Lee, S., Jeong, P.S., Seol, D.W., Son, D., Kim, Y.H., Song, B.S., Sim, B.W., Park, S., and Lee, D.M. (2022). Hyaluronidase 6 Does Not Affect Cumulus-Oocyte Complex Dispersal and Male Mice Fertility. Genes, 13.","DOI":"10.3390\/genes13050753"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.ajpath.2017.01.005","article-title":"Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization Controls Endochondral Ossification through Hyaluronan Metabolism","volume":"187","author":"Shimoda","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1038\/s41467-023-37651-1","article-title":"KIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration","volume":"14","author":"Chen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1016\/j.ajpath.2021.07.008","article-title":"Deletion of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization (HYBID) Results in Attenuation of Osteoarthritis in Mice","volume":"191","author":"Momoeda","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2017.01.049","article-title":"Distribution and function of hyaluronan binding protein involved in hyaluronan depolymerization (HYBID, KIAA1199) in the mouse central nervous system","volume":"347","author":"Yoshino","year":"2017","journal-title":"Neuroscience"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1016\/j.bbrc.2018.07.138","article-title":"Targeted deletion of HYBID (hyaluronan binding protein involved in hyaluronan depolymerization\/ KIAA1199\/CEMIP) decreases dendritic spine density in the dentate gyrus through hyaluronan accumulation","volume":"503","author":"Yoshino","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.celrep.2019.12.001","article-title":"Hyaluronan Degradation by Cemip Regulates Host Defense against Staphylococcus aureus Skin Infection","volume":"30","author":"Dokoshi","year":"2020","journal-title":"Cell Rep."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Peters, A., and Sherman, L.S. (2020). Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21175988"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.1523\/JNEUROSCI.3458-13.2014","article-title":"Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space","volume":"34","author":"Arranz","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1242\/dev.065375","article-title":"Transmembrane protein 2 (Tmem2) is required to regionally restrict atrioventricular canal boundary and endocardial cushion development","volume":"138","author":"Smith","year":"2011","journal-title":"Development"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.devcel.2017.02.005","article-title":"Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover","volume":"40","author":"Lagendijk","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2965","DOI":"10.1242\/dev.139485","article-title":"Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment","volume":"143","author":"Ryckebusch","year":"2016","journal-title":"Development"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/dvdy.106","article-title":"Tmem2 restricts atrioventricular canal differentiation by regulating degradation of hyaluronic acid","volume":"248","author":"Hernandez","year":"2019","journal-title":"Dev. Dyn."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Narita, T., Tobisawa, Y., Bobkov, A., Jackson, M., Ohyama, C., Irie, F., and Yamaguchi, Y. (2023). TMEM2 is a bona fide hyaluronidase possessing intrinsic catalytic activity. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.105120"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Tobisawa, Y., Fujita, N., Yamamoto, H., Ohyama, C., Irie, F., and Yamaguchi, Y. (2021). The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.101281"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Inubushi, T., Nakanishi, Y., Abe, M., Takahata, Y., Nishimura, R., Kurosaka, H., Irie, F., Yamashiro, T., and Yamaguchi, Y. (2022). The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival. PLoS Genet., 18.","DOI":"10.1371\/journal.pgen.1009765"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/14\/1203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:17:56Z","timestamp":1760109476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/14\/1203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,16]]},"references-count":122,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["cells13141203"],"URL":"https:\/\/doi.org\/10.3390\/cells13141203","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,16]]}}}