ACAN mutations as a cause of familial short stature

Abstract

Aggrecan, encoded by ACAN, is a major proteoglycan component of the extracellular matrix in the growth plate and articular cartilage. Aggrecan provides the hydrated gel structure important for the load-bearing properties of joints and plays a key role in cartilage and bone morphogenesis. At least 25 pathological ACAN mutations have been identified in patients with highly variable phenotypes of syndromic or non-syndromic short stature. This review provides an overview of the current understanding of ACAN and the clinical and genetic findings concerning aggrecan-associated diseases.

Keywords: ACAN; aggrecan; bone age; disc herniation; short stature.

Fig. 1.

The structure of ACAN and the position of mutations. The black and white boxes on genomic DNA (gDNA) denote the coding regions on exons 1–18 and the untranslated regions, respectively. The mutations identified in previous studies are shown (NM_013227.3, NP_037359.3). G1, globular domain 1; IGD, interglobular domain; G2, globular domain 2; KS, keratin sulfate attachment domain; CS, chondroitin sulfate attachment domain; G3, globular domain 3. The figure is modified from that of Dateki et al. (11).

Fig. 2.

Spinal phenotype of an ACAN mutation. The radiographic image shows vertebral spicules and severe lumbar deformity (A), and the T2-weighted magnetic resonance image shows multiple lumbar disc herniation (white arrows) (B) in a female patient with a heterozygous ACAN mutation (11).