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Normal Function
The EXT2 gene provides instructions for producing a protein called exostosin-2. This protein is found in a cell structure called the Golgi apparatus, which modifies newly produced enzymes and other proteins. In the Golgi apparatus, exostosin-2 binds to another protein, exostosin-1, to form a complex that modifies a protein called heparan sulfate.
Heparan sulfate is a complex of sugar molecules that is added to proteins. Heparan sulfate helps regulate a variety of body processes, including cell signaling, cell interactions, and immune system functions. Heparan sulfate is also involved in regulating bone formation (ossification) and the growth and specialization (differentiation) of cartilage-forming cells called chondrocytes. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development.
Health Conditions Related to Genetic Changes
Hereditary multiple osteochondromas
Hundreds of changes in the EXT2 gene cause hereditary multiple osteochondromas. Genetic changes that cause disease are called pathogenic variants. People with hereditary multiple osteochondromas develop multiple noncancerous (benign) bone tumors called osteochondromas. EXT2 gene variants cause a form of the condition called hereditary multiple osteochondromas type 2.
Most of the pathogenic variants in the EXT2 gene that cause hereditary multiple osteochondromas are called "loss-of-function variants" because they prevent any functional exostosin-2 proteins from being made. Without functional exostosin-2 to form a complex with exostosin-1, heparan sulfate is not properly modified. This likely disrupts ossification and chondrocyte differentiation, resulting in the formation of the bone tumors seen in people with hereditary multiple osteochondromas.
More About This Health ConditionPotocki-Shaffer syndrome
Certain genetic changes that affect the EXT2 gene are associated with a condition called Potocki-Shaffer syndrome. This condition affects the development of the bones, brain, and other tissues. Characteristic bone abnormalities include multiple osteochondromas and enlarged openings in the two bones that form the top and sides of the skull (enlarged parietal foramina). Other signs and symptoms can include intellectual disabilities, developmental delays, and distinctive facial features.
Potocki-Shaffer syndrome is caused by the deletion of genetic material from the short (p) arm of chromosome 11. In people with this condition, the loss of the EXT2 gene within this region is responsible for multiple osteochondromas. The deletion likely reduces the number of exostosin-2 proteins, which disrupts the processing of heparan sulfate. Without enough functional heparan sulfate, it is likely that ossification and the differentiation of chondrocytes are impaired, resulting in multiple osteochondromas.
The loss of additional genes in the deleted region likely contributes to the other features of Potocki-Shaffer syndrome. For example, the loss of the ALX4 gene results in enlarged parietal foramina, and the deletion of the PHF21A gene causes intellectual disabilities and distinctive facial features.
More About This Health ConditionOther disorders
Pathogenic variants in the EXT2 gene have been found to cause seizures-scoliosis-macrocephaly syndrome. Affected individuals have seizures, an abnormal curvature of the spine (scoliosis), an unusually large head (macrocephaly), intellectual disabilities, little or no speech, low muscle tone (hypotonia), and other skeletal abnormalities. The EXT2 gene variants that are associated with seizures scoliosis-macrocephaly syndrome occur in both copies of the gene in each cell and lead to the substitution of one protein building block (amino acid) for another in the exostosin-2 protein. These changes reduce the number of functional exostosin-2 proteins that are produced, which likely disrupts the normal modification of heparan sulfate. It is unclear how this disruption leads to the signs and symptoms of the condition.
Other Names for This Gene
- exostosin 2
- SOTV
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Clement ND, Porter DE. Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender. Scott Med J. 2014 Feb;59(1):35-44. doi: 10.1177/0036933013518150. Epub 2014 Jan 10. Citation on PubMed
- Farhan SM, Wang J, Robinson JF, Prasad AN, Rupar CA, Siu VM; FORGE Canada Consortium; Hegele RA. Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses. J Med Genet. 2015 Oct;52(10):666-75. doi: 10.1136/jmedgenet-2015-103279. Epub 2015 Aug 5. Citation on PubMed
- Jochmann K, Bachvarova V, Vortkamp A. Heparan sulfate as a regulator of endochondral ossification and osteochondroma development. Matrix Biol. 2014 Feb;34:55-63. doi: 10.1016/j.matbio.2013.11.003. Epub 2013 Dec 24. Citation on PubMed
- Labonne JD, Vogt J, Reali L, Kong IK, Layman LC, Kim HG. A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies. Am J Med Genet A. 2015 Dec;167A(12):3011-8. doi: 10.1002/ajmg.a.37344. Epub 2015 Sep 3. Citation on PubMed
- Leisico F, Omeiri J, Le Narvor C, Beaudouin J, Hons M, Fenel D, Schoehn G, Coute Y, Bonnaffe D, Sadir R, Lortat-Jacob H, Wild R. Structure of the human heparan sulfate polymerase complex EXT1-EXT2. Nat Commun. 2022 Nov 19;13(1):7110. doi: 10.1038/s41467-022-34882-6. Citation on PubMed
- McCormick C, Duncan G, Goutsos KT, Tufaro F. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):668-73. doi: 10.1073/pnas.97.2.668. Citation on PubMed or Free article on PubMed Central
- Musso N, Caronia FP, Castorina S, Lo Monte AI, Barresi V, Condorelli DF. Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas. Cancer Genet. 2015 Mar;208(3):62-7. doi: 10.1016/j.cancergen.2015.01.002. Epub 2015 Jan 16. Citation on PubMed
- Romeike BF, Wuyts W. Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature. Clin Neuropathol. 2007 Jan-Feb;26(1):1-11. doi: 10.5414/npp26001. Citation on PubMed
- Sefcik R, Earl D. Hereditary Multiple Osteochondromas. 2000 Aug 3 [updated 2026 Jan 29]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1235/ Citation on PubMed
- Wakui K, Gregato G, Ballif BC, Glotzbach CD, Bailey KA, Kuo PL, Sue WC, Sheffield LJ, Irons M, Gomez EG, Hecht JT, Potocki L, Shaffer LG. Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki-Shaffer syndrome. Eur J Hum Genet. 2005 May;13(5):528-40. doi: 10.1038/sj.ejhg.5201366. Citation on PubMed
- Wuyts W, Waeber G, Meinecke P, Schuler H, Goecke TO, Van Hul W, Bartsch O. Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects. Eur J Hum Genet. 2004 May;12(5):400-6. doi: 10.1038/sj.ejhg.5201163. Citation on PubMed
- Yang M, Xie H, Xu B, Xiang Q, Wang H, Hu T, Liu S. Identification of a novel EXT2 frameshift mutation in a family with hereditary multiple exostoses by whole-exome sequencing. J Clin Lab Anal. 2021 Sep;35(9):e23968. doi: 10.1002/jcla.23968. Epub 2021 Aug 17. Citation on PubMed
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