The gene products of human EXT1 and EXT2 are endoplasmic reticulum localized type II transmembrane glycoproteins. In vivo they form a stable hetero-oligomeric complex that accumulates in the Golgi apparatus, where it is involved in heparan sulphate proteoglycan (HSPG) biosynthesis. The EXT1/EXT2 complex catalyses the elongation of the HS chain, which is subsequently deacetylated, sulphated and epimerized resulting in a large spectrum of structural heterogenic HS chains. The sulphation pattern of HS chains is critical for binding specific proteins. Several growth factors have conserved patterns of basic amino acids for binding to HSPGs, which is crucial for proper signaling.
Germline alterations in EXT1 and EXT2 are a cause of hereditary multiple exostoses type 1 (EXT1) and type II, respectively. EXT is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3 (minor locus), respectively. EXT is a heterogeneous autosomal dominant disorder primarily affecting endochondral bone during growth. The disease is characterized by formation of numerous cartilage-capped, benign bone tumors (osteocartilaginous exostoses or osteochondromas) that are often accompanied by skeletal deformities and short stature. In a small percentage of cases exostoses have exhibited malignant transformation resulting in an osteosarcoma or chondrosarcoma. Osteochondromas development can also occur as a sporadic event. EXT1 mutations include nucleotide substitutions (54%), small deletions (27%) and small insertions (16%), of which the majority is predicted to result in a truncated or non-functional protein. EXT2 mutations include nucleotide substitutions (57%), small deletions (19%) and small insertions (24%), of which the majority is predicted to result in a truncated or non-functional protein.
Defects in EXT1 are the cause of multiple exostoses observed in Langer-Giedon syndrome (LGS; also known as trichorhinophalangeal syndrome type 2 (TRPS2). It is a contiguous gene syndrome due to deletions in chromosome 8q24.1 and resulting in the loss of functional copies of EXT1 and TRPS1.
Defects in EXT1 are a cause of chondrosarcoma (CHDSA). It is a malignant neoplasm derived from cartilage cells. Chondrosarcomas range from slow-growing non-metastasizing lesions to highly aggressive metastasizing sarcomas.
Defects in EXT2 are the cause of multiple exostoses observed in Potocki-Shaffer syndrome. It is a contiguous gene syndrome due to proximal deletion of chromosome 11p11.2, including EXT2 and ALX4.
No EXT1/EXT2 somatic mutations were found in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested.
References (open access):
Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 Multiple Osteochondromas families. Jennes I, de Jong D, Mees K, Hogendoorn PC, Szuhai K, Wuyts W. BMC Med Genet. 2011 Jun 26;12:85.
A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Matsumoto K, Irie F, Mackem S, Yamaguchi Y. Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10932-7.
Genomic profiling of chondrosarcoma: chromosomal patterns in central and peripheral tumors. Hallor KH, Staaf J, Bovée JV, Hogendoorn PC, Cleton-Jansen AM, Knuutila S, Savola S, Niini T, Brosjö O, Bauer HC, Vult von Steyern F, Jonsson K, Skorpil M, Mandahl N, Mertens F. Clin Cancer Res. 2009 Apr 15;15(8):2685-94.