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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Aug 26, 2015; 6(3): 110-120
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.110
Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism
Barbara Triggs-Raine, Marvin R Natowicz
Barbara Triggs-Raine, Departments of Biochemistry and Medical Genetics, and Pediatrics and Child Health, University of Manitoba, Winnipeg MB R3E 0J9, Canada
Barbara Triggs-Raine, Manitoba Institute of Child Health, Winnipeg MB R3E 3P4, Canada
Marvin R Natowicz, Pathology and Laboratory Medicine, Genomic Medicine, Neurological and Pediatrics Institutes, Cleveland Clinic, Cleveland, OH 44195, United States
Author contributions: Triggs-Raine B conceived and wrote the manuscript; Natowicz MR critically reviewed and revised the manuscript.
Supported by Canadian Institutes of Health Research (to Triggs-Raine B).
Conflict-of-interest statement: The authors have no conflicts of interest to declare related to this research.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Barbara Triggs-Raine, Departments of Biochemistry and Medical Genetics, and Pediatrics and Child Health, University of Manitoba, 745 Bannatyne Ave, Winnipeg MB R3E 0J9, Canada. barbara.triggs-raine@umanitoba.ca
Telephone: +1-204-7893218 Fax: +1-204-7893900
Received: March 27, 2015
Peer-review started: March 28, 2015
First decision: April 27, 2015
Revised: May 8, 2015
Accepted: July 16, 2015
Article in press: July 17, 2015
Published online: August 26, 2015
Processing time: 152 Days and 5.4 Hours
Abstract

Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two genetic disorders of hyaluronan metabolism have been reported in humans: HYAL1 deficiency (Mucopolysaccharidosis IX) in four individuals with joint pathology as the predominant phenotypic finding and HAS2 deficiency in a single person having cardiac pathology. However, inherited disorders and induced mutations affecting hyaluronan metabolism have been characterized in other species. Overproduction of hyaluronan by HAS2 results in skin folding and thickening in shar-pei dogs and the naked mole rat, whereas a complete deficiency of HAS2 causes embryonic lethality in mice due to cardiac defects. Deficiencies of murine HAS1 and HAS3 result in a predisposition to seizures. Like humans, mice with HYAL1 deficiency exhibit joint pathology. Mice lacking HYAL2 have variably penetrant developmental defects, including skeletal and cardiac anomalies. Thus, based on mutant animal models, a partial deficiency of HAS2 or HYAL2 might be compatible with survival in humans, while complete deficiencies of HAS1, HAS3, and HYAL3 may yet be recognized.

Keywords: Hyaluronidase, Hyaluronan, Hyaluronidase 1, Mucopolysaccharidosis, Hyaluronidase 2, Hyaluronan synthase 2

Core tip: This manuscript summarizes the phenotypes that have been associated with alterations in hyaluronan synthesis or degradation. It should serve as a reference for those who are considering an alteration in hyaluronan metabolism as the cause of a genetic condition.