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Mutations in the gene for cartilage oligomeric matrix protein (COMP) bring some forms of multiple epiphyseal dysplasia (MED) and bring pseudoachondroplasia (PSACH). Early-onset osteoarthrosis and mild-to-severe short-limb dwarfism occur with PSACH and MED. In 14 families with MED or PSACH phenotypes COMP mutations have been identified. In the region of the COMP gene that encodes the calmodulin-like repeat elements mutations thought likely to bring with them single amino acid deletions/substitution have been found in people with moderate to sever PSACH. In the same domain a missense mutation that brought MED Fairbank was found. It appears that there is phenotype overlap for MED and PSACH. The carboxyl-terminal domain is a factor in the structure and /or function of COMP.

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are two human autosomal dominant skeletal dysplasias characterized by variable short stature, joint laxity and early-onset degenerative joint disease. Both disorders can result from mut-ations in the gene for cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein. About one-third of PSACH cases result from heterozygosity for deletion of one codon within a very short triplet repeat, (GAC)[sub 5], which encodes five consecutive aspartic acid residues within the calmodulin-like region of the COMP protein. We have identified two expansion mut-ations in this repeat: an MED patient carrying a (GAC)[sub 6] allele and a PSACH patient carrying a (GAC)[sub 7] allele. These are among the shortest disease-causing triplet repeat expansion mutations described thus far, and are the first identified in a GAC repeat. A unique feature of this sequence is that expansion as well as shortening of the repeat can cause the same disease. In cartilage, both patients have rough endoplasmic reticulum inclusions in chondrocytes. The inclusions are also present in tendon tissue and can be reproduced in cultured tendon cells, suggesting that the pathophysiology of disease is similar in both cartilage and tendon. [ABSTRACT FROM AUTHOR]