Multiple Epiphyseal Dysplasia - Cause

Cause

In the dominant form, mutations in five genes are causative: COMP (chromosome 19), COL9A1 (chromosome 6), COL9A2 (chromosome 1), COL9A3 (chromosome 20), and MATN3 (chromosome 2). However, in approximately 10%-20% of all samples analyzed, a mutation cannot be identified in any of the five genes above, suggesting that mutations in other as-yet unidentified genes are also involved in the pathogenesis of dominant MED. The COMP gene is mutated in 70% of the molecularly confirmed MED patients. Mutations are located in the exons encoding the type III repeats (exons 8-14) and C-terminal domain (exons 15-19). The most common mutations in COL9A1 are located in exons 8-10, in COL9A2 in exons 2-4, and in COL9A3 in exons 2-4. Altogether, those mutations cover 10% of the patients. Other 20% of affected people have mutations in MATN3 gene, all found within exon 2. In order to this findings, the following testing regime has been recommended by the European Skeletal Dysplasia Network:

• Level 1: COMP (exons 10-15) and MATN3 (exon 2)
• Level 2: COMP (exons 8 & 9 and 16-19)
• Level 3: COL9A1 (exon 8), COL9A2 and COL9A3 (exon 3)

All those genes are involved in the production of the extracellular matrix (ECM). The role of COMP gene still remains unclear. It is a noncollagenous protein of the ECM. Mutations in this gene can also cause the pseudoachondroplasia (PSACH). It should play a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins and can be part of the interaction of the chondrocytes with the matrix through. It is a potent suppressor of apoptosis in chondrocytes and can suppress apoptosis. Another one of it roles is maintaining a vascular smooth muscle cells contractile under physiological or pathological stimuli Since 2003, the European Skeletal Dysplasia Network has used an on-line system to do diagnose cases referred to the network prior to mutation analysis in order to study the different mutations causing PSACH or MED.

COL9A1, COL9A2, COL9A3 are genes coding for collagen type IX, that is a component of hyaline cartilage. MATN3 protein may play a role in the formation of the extracellular filamentous networks and in the development and homeostasis of cartilage and bone.

In the recessive form, DTDST gene is mutated almost in 90% of the patients. It is also known as SLC26A2. It is a sulfate transporter, transmembrane glycoprotein implicated in several chondrodysplasias. It is important for sulfation of proteoglycans and matrix organization.