ClinVar Genomic variation as it relates to human health

Short stature (present) , Genu valgum (present) , Micromelia (present) , Brachydactyly (present) , Abnormal upper limb metaphysis morphology (present) , Abnormal epiphysis morphology (present) , Short long bone (present) , Spondyloepiphyseal dysplasia (present) , Spondyloepimetaphyseal dysplasia (present) (less)

In 5 unrelated patients with pseudoachondroplasia (PSACH; 177170), including 1 from a family originally reported by Hall and Dorst (1969), Hecht et al. (1995) identified a 3-bp deletion removing 1 of the 5 GAC repeat sequences at cDNA nucleotides 1430-1445 of the COMP gene. This resulted in the loss of an aspartate residue in a calcium-binding site. In 2 sporadic patients and affected members of 5 families with PSACH, Briggs et al. (1998) identified heterozygosity for a 3-bp deletion (delGAC 1430-1444) in exon 13 of the COMP gene, resulting in removal of 1 of 5 consecutive aspartic acid residues corresponding to codons 469 to 473 within the seventh calmodulin-like repeat. The authors noted that the repeated nature of the GAC sequence did not allow precise determination of the codon that was deleted in the patients. In 3 sporadic patients with PSACH, Ikegawa et al. (1998) identified heterozygosity for a 3-bp deletion within the (GAC)5 trinucleotide repeat region in exon 13. Ikegawa et al. (1998) noted that, like the previously reported patients with this mutation, the phenotype was severe in all 3 patients, their adult heights being less than 110 cm. Briggs and Chapman (2002) reviewed mutations in the COMP gene resulting in PSACH and, using nucleotide numbering from the start site of translation, designated this nucleotide change as 1405-1419 delGAC and the corresponding protein change as delD(469-473). This mutation is thought to account for approximately one-third of PSACH patients. It is a contraction of a short trinucleotide repeat; expansion of this repeat to (GAC)6 and (GAC)7 are represented by 2 other entries, 600310.0012 and 600310.0011, respectively (Delot et al., 1999). Mutation Function Deletion of 1 of the 5 asp codons in the type 3 calcium-binding domain of COMP essentially deletes the single asp470 spacer between calcium-binding loops 10 and 11. Kleerekoper et al. (2002) created recombinant mutant COMP proteins that carried a deletion of asp470, mimicking the deletion found in PSACH patients, and found that this deletion decreased the calcium binding capacity of COMP. Calcium binding by this domain is required to nucleate folding. The authors predicted that persistence of the unstructured state of the mutated calcium-binding domain would lead to retention of COMP in the rough endoplasmic reticulum of differentiated PSACH and EDM1 chondrocytes. Dinser et al. (2002) developed a cell culture model of pseudoachondroplasia by expressing mutant COMP (D469del) in bovine primary chondrocytes. They showed that mutant COMP exerts its deleterious effects through both intra- and extracellular pathogenic pathways. Overexpression of mutant COMP led to a dose-dependent decrease in cellular viability. The secretion of mutant COMP was markedly delayed, presumably due to a prolonged association with chaperones in the endoplasmic reticulum. The extracellular matrix lacked organized collagen fibers and showed amorphous aggregates formed by mutant COMP. Thus, pseudoachondroplasia appeared to be an endoplasmic reticulum storage disease, most likely caused by improper folding of mutant COMP. The growth failure of patients with pseudoachondroplasia may be explained by an increased cell death of growth-plate chondrocytes. Dominant interference of the mutant protein with collagen fiber assembly could contribute to the observed failure of the extracellular matrix of cartilage and tendons. (less)