The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases

Abstract

The large chondroitin sulphated proteoglycan aggrecan (ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms. This review discusses the known human and animal aggrecanopathies in the context of clinical presentation and potential disease mechanisms.

Keywords: Aggrecan; Cartilage; Chondrodysplasia; Osteochondritis dissecans; Skeletal dysplasia.

Fig. 1

Schematic of the aggrecan showing the location of mutations and functions of the individual domains. Each of the seven human mutations is indicated (top) in the relevant domains (middle) that each has a specific function (bottom). Key: ISS = idiopathic short stature; SED = spondyloepiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia; OCD = osteochondritis dysplasia; G1 = globular domain 1; G2 = globular domain 2; G3 = globular domain 3; KS = keratin sulphate attachment domain; CS = chondroitin sulphate attachment domain