ArticleAmerican journal of human genetics2001
Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity.
Article in American journal of human genetics, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 76 citations in OpenAlex.
- Transplantation immunology: paradigm shift from systemic suppression to microenvironment remodeling and precision modulation.Frontiers in cell and developmental biology · 2026Review
- The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structure of the human heparan sulfate polymerase complex EXT1-EXT2.Nature communications · 2022Article
- Osteochondroma formation is independent of heparanase expression as revealed in a mouse model of hereditary multiple exostoses.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2022Article
- Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease.American journal of physiology. Cell physiology · 2022Review
- An Easy-to-Use Approach to Detect CNV From Targeted NGS Data: Identification of a Novel Pathogenic Variant in MO Disease.Frontiers in endocrinology · 2022Article
- Hereditary multiple osteochondromas in Jordanian patients: Mutational and immunohistochemical analysis ofOncology letters · 2021Article
- Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis.Frontiers in genetics · 2021Review
- [Cartilage tumors: morphology, genetics, and current aspects of target therapy].Der Pathologe · 2020Review
- General Base Swap Preserves Activity and Expands Substrate Tolerance in Hedgehog Autoprocessing.Journal of the American Chemical Society · 2019Article
- Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas.Molecules (Basel, Switzerland) · 2018Article
- The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses.Matrix biology : journal of the International Society for Matrix Biology · 2018Review
- Domains with highest heparan sulfate-binding affinity reside at opposite ends in BMP2/4The Journal of biological chemistry · 2018Article
- Heparan sulfate antagonism alters bone morphogenetic protein signaling and receptor dynamics, suggesting a mechanism in hereditary multiple exostoses.The Journal of biological chemistry · 2018Article
- Hereditary multiple exostoses: are there new plausible treatment strategies?Expert opinion on orphan drugs · 2018Article
- Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference.Connective tissue research · 2018Article
- Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.Current osteoporosis reports · 2017Review
- Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice.PLoS genetics · 2017Article
- Article
- Detection of exostosin glycosyltransferase gene mutations in patients with non-hereditary osteochondromas of the mandibular condyle.Molecular and clinical oncology · 2016Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Hereditary multiple exostoses (HME), a dominantly inherited genetic disorder characterized by multiple cartilaginous tumors, is caused by mutations in members of the EXT gene family, EXT1 or EXT2. The corresponding gene products, exostosin-1 (EXT1) and exostosin-2 (EXT2), are type II transmembrane glycoproteins which form a Golgi-localized heterooligomeric complex that catalyzes the polymerization of heparan sulfate (HS). Although the majority of the etiological mutations in EXT are splice-site, frameshift, or nonsense mutations that result in premature termination, 12 missense mutations have also been identified. Furthermore, two of the reported etiological missense mutations (G339D and R340C) have been previously shown to abrogate HS biosynthesis (McCormick et al. 1998). Here, a functional assay that detects HS expression on the cell surface of an EXT1-deficient cell line was used to test the remaining missense mutant exostosin proteins for their ability to rescue HS biosynthesis in vivo. Our results show that EXT1 mutants bearing six of these missense mutations (D164H, R280G/S, and R340S/H/L) are also defective in HS expression, but surprisingly, four (Q27K, N316S, A486V, and P496L) are phenotypically indistinguishable from wild-type EXT1. Three of these four "active" mutations affect amino acids that are not conserved among vertebrates and invertebrates, whereas all of the HS-biosynthesis null mutations affect only conserved amino acids. Further, substitution or deletion of each of these four residues does not abrogate HS biosynthesis. Taken together, these results indicate that several of the reported etiological mutant EXT forms retain the ability to synthesize and express HS on the cell surface. The corresponding missense mutations may therefore represent rare genetic polymorphisms in the EXT1 gene or may interfere with as yet undefined functions of EXT1 that are involved in HME pathogenesis.
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