This site complies with the HONcode standard for trustworthy health information:
verify here.

Spondyloepimetaphyseal Dysplasia – Aggrecan

« Back to Volume 25, Issue 1, June 2009 - Table of Contents

Despite considerable progress in delineating the human chondrodysplasias, there are still many distinctive dwarfing clinical phenotypes for which no mutant gene has been found; conversely there are genes that encode proteins important for linear bone growth for which few if any chondrodysplasia-causing mutations have been identified. The report by Tompson et al helps to establish a new link in this context.

A family is described with extreme short stature, brachydactyly, distinctive facies and radiographs consistent with spondyloepimetaphyseal dysplasia (SEMD) in 3 of 4 siblings; the parents had average stature suggesting autosomal recessive inheritance (Figure). Consanguinity was denied, but both parents came from a small village in Mexico. Whole-genome single-nucleotide polymorphism (SNP) analysis of the 2 affected siblings and 1 unaffected sibling revealed several 10-20 cM blocks of shared alleles suggesting a common ancestry and raising the possibility that the affected siblings may have inherited an ancestral mutation that was transmitted through both parents. If so, then they would be expected to be homozygous for the mutation, ie, identity by descent, and the mutation would be expected to map to the genetic region or interval that was shared by the affected siblings but not by the unaffected sibling. A single genetic interval on chromosome 15 met these criteria; it contained 193 annotated or characterized genes and 103 unannotated genes.

Clinical Phenotype.
In the top image, the back row from left to right shows II-1 (23 years old [yo]) and I-I (58 yo), respectively, and the front row from left to right shows II-2 (19 yo), II-3 (16 yo), and II-4 (26 yo), respectively. Note the telescoping fingers of II-3.

When the investigators narrowed down their search to genes expressed only or disproportionately highly in cartilage, because of its essential role in endochondral bone growth, 2 genes emerged: chondroitin sulfate proteoglycan 4 (CSPG4) and aggrecan (AGAN). Sequence analysis of AGAN revealed homozygosity in the affected siblings for a missense mutation that substituted an asparagine for an aspartic acid residue at position 2267 (A2267N) in the C-terminal G3 globular domain of aggrecan. The parents were both heterozygotes for the mutation.

The A2267 aspartic acid is highly conserved across species and even across different proteoglycans that share a similar globular domain; it has been implicated in mediating molecular interactions between aggrecan and other cartilage matrix constituents, such as tenascin. To explore the molecular consequences of the mutation, the authors expressed the normal and mutant G3 domain proteins in cells and then analyzed them biochemically. They observed that the mutant G3 domain was secreted normally, but there was evidence of disturbed binding of the mutant G3 domain to tenascin compared to normal. They also showed that the asparagine residue in the mutant AGAN G3 domain is capable of being glycosylated, which could potentially alter functions as well as biosynthesis and stability of AGAN.

The authors noted that haploinsufficiency due to heterozygous mutations of AGAN has recently been reported in another rare condition, spondyloepiphyseal dysplasia (SED) Kimberley. This is a milder condition that typically presents with mild short stature and precocious osteoarthritis. They also point out that the genomic region to which AGAN has been mapped through genome-wide association studies has been linked to normal height variation.

Tompson SW, Merriman N, Funari V, et al. A recessive skeletal dysplasia, SEMD aggrecan type results from a missense mutation affecting the C-type lectin domain of aggrecan. A J Hum Genet. 2009;84:72-79.

Editor’s Comment

Given its abundance in growth plate cartilage and presumed importance to endochondral bone growth, the difficulty finding mutations of AGAN in chondrodysplasias is surprising. It would have been interesting to study cartilage tissue, which presumably was not available, since it might have provided additional clues as to how the mutation disrupts cartilage biology. A factor not discussed is the possibility that alterations in cartilage aggrecan could alter growth factor signaling within the growth plate, as proteoglycans are thought to influence the mobility and local concentrations of growth factors in cartilage and possibility their presentation to transmembrane receptors.

William A. Horton, MD

« Back to Volume 25, Issue 1, June 2009 - Table of Contents

Last Updated: 6/12/2009