Hereditary multiple exostoses, Osteochondroma - EXT1 and EXT2 genes
Hereditary multiple exostosis is a skeletal genetic disease characterized by an early development of osteochondromas, usually multiple, with a tendency towards malignancy, mainly of the diaphyses of the limbs bones. It can also involve bones of the waist and, to a lesser degree, vertebrae, sternum, spine and bones of the carpus and tarsus. Multiple exostosis can interrupt the growth of bones and can cause alterations in the growth of the arms, hands and legs, leading to short stature. Often, these bone growth problems do not affect both sides equally, which results in an irregular length of the limbs. Hip dysplasia caused by exostosis can cause difficulty walking and general malaise. In addition, exostosis can cause pain, limited range of motion of the joint, as well as pressure on the nerves, blood vessels, spinal cord and tissues surrounding the exostoses. Although exostosis is not present at birth, approximately 96% of affected persons develop multiple exostosis after 12 years of age.
This process is due to alterations in the EXT1 genes, located in the long arm of chromosome 8 (8q24.11) and EXT2, located in the short arm of chromosome 11 (11p12-p11), and hypothetically, in EXT3. If the disease is due to a mutation in the EXT1 gene it is called hereditary multiple exostosis type 1. The mutations in the EXT2 gene give rise to hereditary multiple exostosis type 2.
These genes encode the proteins exostosin-1 and exostosin-2, respectively. The two exostosine proteins bind together and form a complex that is found in the Golgi apparatus. In the Golgi apparatus, the products of the EXT1 and EXT2 genes have glycosyltransferase activity and are involved in the biosynthesis of heparan sulfate. Heparan sulfate is involved in the regulation of a variety of body processes including blood coagulation and angiogenesis. It also has a role in the metastasis of cancer cells.
Approximately 200 mutations in the EXT1 gene have been identified in people with hereditary multiple exostosis type 1 and more than 90 mutations in the EXT2 gene in people with hereditary multiple exostosis type 2. Most of these mutations are known as mutations of "loss of function", since they inhibit the coding of the functional proteins exostosin-1 and exostosin-2. The loss of these functional proteins inhibits the formation of an exostosin-1 / exostosin-2 complex and the modification of heparan sulfate. Although heparan sulfate is involved in many bodily processes, it is not clear how the absence of this protein contributes to the development of exostosis. Approximately 15% of people with hereditary multiple exostosis do not have any mutation in the EXT1 or EXT2 gene. In these cases the cause of the disease is unknown.
Several studies have established a certain phenotype-genotype correlation where mutations in the EXT1 gene are associated with a more severe phenotype and an increased risk of chondrosarcoma than those that occur in EXT2. In the EXT1 gene, the largest number of mutations, approximately one third, are located in exon 2. In the EXT2 gene, they are concentrated mainly in exons 2, 3, 4 and 7.
Hereditary multiple exostosis is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the disease. In some cases, an affected person inherits the mutation of an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of the disease in their family.
Tests performed in IVAMI: in IVAMI we performed the detection of mutations associated with hereditary multiple exostosis, by means of the complete PCR amplification of the exons of the EXT1 and EXT2 genes, respectively, and their subsequent sequencing. It is recommended to start the study with the EXT1 gene, responsible for the majority of cases, and continue, if necessary, for the EXT2 gene. In the study of each gene, the exons where the greatest number of mutations are concentrated (exon 2 in the EXT1 gene and exons 2, 3, 4 and 7 in the EXT2 gene) will be amplified and sequenced, stopping the study in case of positive result, with the consequent saving of time and costs. In case of not detecting mutations in both genes, we performed the real-time quantitative PCR test (qPCR Real Time) for the detection of possible deletions.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).