{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:03:04Z","timestamp":1790866984706,"version":"4.1.0"},"reference-count":24,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,5,25]]},"abstract":"<jats:p>\n                    Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix, is important in cell migration during embryonic development, cellular proliferation, and differentiation and has a structural role in connective tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal hyaluronidase, and a congenital deficiency of hyaluronidase has been thought to be incompatible with life. However, a patient with a deficiency of serum hyaluronidase, now designated as mucopolysaccharidosis IX, was recently described. This patient had a surprisingly mild clinical phenotype, including notable periarticular soft tissue masses, mild short stature, an absence of neurological or visceral involvement, and histological and ultrastructural evidence of a lysosomal storage disease. To determine the molecular basis of mucopolysaccharidosis IX, we analyzed two candidate genes tandemly distributed on human chromosome 3p21.3 and encoding proteins with homology to a sperm protein with hyaluronidase activity. These genes,\n                    <jats:italic>HYAL1<\/jats:italic>\n                    and\n                    <jats:italic>HYAL2<\/jats:italic>\n                    , encode two distinct lysosomal hyaluronidases with different substrate specificities. We identified two mutations in the\n                    <jats:italic>HYAL1<\/jats:italic>\n                    alleles of the patient, a 1412G \u2192 A mutation that introduces a nonconservative amino acid substitution (Glu268Lys) in a putative active site residue and a complex intragenic rearrangement, 1361del37ins14, that results in a premature termination codon. We further show that these two hyaluronidase genes, as well as a third recently discovered adjacent hyaluronidase gene,\n                    <jats:italic>HYAL3<\/jats:italic>\n                    , have markedly different tissue expression patterns, consistent with differing roles in HA metabolism. These data provide an explanation for the unexpectedly mild phenotype in mucopolysaccharidosis IX and predict the existence of other hyaluronidase deficiency disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.96.11.6296","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:39:15Z","timestamp":1027679955000},"page":"6296-6300","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":173,"title":["Mutations in\n                    <i>HYAL1<\/i>\n                    , a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX"],"prefix":"10.1073","volume":"96","author":[{"given":"Barbara","family":"Triggs-Raine","sequence":"first","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology and Human Genetics, University of Manitoba, Winnipeg, MB R3E OW3, Canada; Division of Medical Genetics, Shriver Center for Mental Retardation, Waltham, MA, 02452; and Harvard Medical School and Massachusetts General Hospital, Boston, MA 02254"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Salo","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology and Human Genetics, University of Manitoba, Winnipeg, MB R3E OW3, Canada; Division of Medical Genetics, Shriver Center for Mental Retardation, Waltham, MA, 02452; and Harvard Medical School and Massachusetts General Hospital, Boston, MA 02254"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology and Human Genetics, University of Manitoba, Winnipeg, MB R3E OW3, Canada; Division of Medical Genetics, Shriver Center for Mental Retardation, Waltham, MA, 02452; and Harvard Medical School and Massachusetts General Hospital, Boston, MA 02254"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandy A.","family":"Wicklow","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology and Human Genetics, University of Manitoba, Winnipeg, MB R3E OW3, Canada; Division of Medical Genetics, Shriver Center for Mental Retardation, Waltham, MA, 02452; and Harvard Medical School and Massachusetts General Hospital, Boston, MA 02254"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin R.","family":"Natowicz","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology and Human Genetics, University of Manitoba, Winnipeg, MB R3E OW3, Canada; Division of Medical Genetics, Shriver Center for Mental Retardation, Waltham, MA, 02452; and Harvard Medical School and Massachusetts General Hospital, Boston, MA 02254"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1999,5,25]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560040902"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.4052\/tigg.8.419"},{"key":"e_1_3_3_3_2","first-page":"23","volume":"242","author":"Fraser J R E","year":"1997","unstructured":"J R E Fraser, T C Laurent J Intern Med 242, 23\u201327 (1997).","journal-title":"J Intern Med"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2796.1997.00171.x"},{"key":"e_1_3_3_5_2","first-page":"60","volume":"143","author":"Roden L","year":"1989","unstructured":"L Roden, P Campbell, J R E Fraser, T C Laurent, H Pertoft, J N Thompson Ciba Found Symp 143, 60\u201386 (1989).","journal-title":"Ciba Found Symp"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199610033351405"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(68)90188-5"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(93)80873-S"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6773"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1997.5158"},{"key":"e_1_3_3_11_2","first-page":"1487","volume":"56","author":"Wei M","year":"1996","unstructured":"M Wei, F Latif, S Bader, V Kashuba, J Y Chen, F-M Duh, Y Sekido, C-C Lee, L Geil, I Kuzmin, et al. 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