Dominant multiple epiphyseal dysplasia is caused by a mutation in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, many organ systems of the body can be affected.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Dominant multiple epiphyseal dysplasia type 1 is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. The majority of cases (more than 70%) of multiple epiphyseal dysplasia are caused by mutations in the COMP gene. Investigators have determined that the gene is located on the short arm (p) of chromosome 19 (19p13.11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
Dominant multiple epiphyseal dysplasia type 2 is caused by mutations in the collagen type IX alpha-2 (COL9A2) gene. The gene is located on the short arm of chromosome 1 (1p34.2).
Dominant multiple epiphyseal dysplasia type 3 is caused by mutations in the collagen type IX alpha-3 (COL9A3) gene. The gene is located on the long arm 20q13.33.
Dominant multiple epiphyseal dysplasia type 5 gene is caused by mutations in the matrilin 3 (MATN3) gene. The gene is located on the short arm of chromosome 2 (2p24.1).
Dominant multiple epiphyseal dysplasia type 6 is caused by mutations in the collagen type IX alpha-1 (COL9A1) gene. The gene is located on the long arm of chromosome 6 (6q13).
The COMP and MATN3 genes create (encode) proteins that are found in the extracellular matrix, which is a network of tissue that provides support to cells. The proteins encoded by these genes are found in the part of the extracellular matrix surrounding cells that make up the ligaments or tendons, as well as nearby cartilage-forming cells known as chondrocytes. The exact functions of these proteins are not fully understood.
The COL9A2, COL9A3, and COL9A1 genes create (encode) various parts of type IX collagen, a protein that is essential to the development and strengthening of connective tissue. Connective tissue, which is the material between cells of the body, is made up of collagen of which there are several different varieties found in the body. Type IX collagen is an important part of cartilage.
Researchers have determined that the progression and severity of dominant multiple epiphyseal dysplasia may vary based upon the gene involved and the specific mutation present in a gene as well as the specific location of the mutation in the gene. This is known as genotype-phenotype correlation. For example, the three genes associated with type IX collagen are more likely to have severe joint involvement with the knees, while the hips are spared or only mildly affected. MATN3 mutations are associated with hip abnormalities that are more severe than those seen in individuals with a COL9A2 mutation, but less severe than those seen in individuals in a COMP mutation. Significant involvement of the head of the thigh bone (femoral epiphysis) is more likely with COMP mutations than other mutations. Researchers are studying these disorders to further understand the specific genotype-phenotype correlations.
Although five different genes known to cause dominant multiple epiphyseal dysplasia, many cases cannot be linked to any of these genes suggesting that additional, as-yet-unidentified genes may also cause the disorder. The known genes are estimated to account for less than half of the overall cases of this disorder.