Table 1.
Mutations Affecting Aggrecan Synthesis, Posttranslational Modification, or Interactions
| Type | Disorder or Mutation | Heterozygous Phenotype | Homozygous Phenotype | Reference |
|---|---|---|---|---|
| Loss of aggrecan (null) | Cartilage matrix deficiency mouse, Bc (cmdbc) | Mild dwarfism | Lethal chondrodysplasia | Krueger et al. 1999 |
| Loss of aggrecan (functional null) | Cartilage matrix deficiency mouse (cmd) | Mild dwarfism, shortened life span | Lethal chondrodysplasia | Watanabe H et al. 1994; Watanabe H, Nakata, et al. 1997 |
| Bulldog mutation, Dexter cattle (ACAN, two alleles) | Short limb dwarfism | Lethal chondrodysplasia | Cavanagh et al. 2007 | |
| SED, Kimberley type | SED, early OA | ? | Gleghorn et al. 2005 | |
| Nanomelia chick | Shortened legs | Lethal chondrodysplasia | Li et al. 1993 | |
| Impaired aggrecan glycosylation | Schneckenbecken syndrome (nucleotide-sugar transporter SLC35D1) | — | Lethal skeletal dysplasia | Hiraoka et al. 2007 |
| Chondroitin sulfate N-acetylgalactosaminyltransferase 1 knock-out mouse (CSGalNAcT-1) | — | Dwarfism | Sato et al. 2011; Watanabe Y et al. 2010 | |
| Impaired aggrecan sulfation | Diastrophic dysplasia (DTDST, SLC26A2) | — | Short stature, joint contractures, cleft palate | Hästbacka et al. 1994 |
| MED, recessive (DTDST, SLC26A2) | — | MED | Superti-Furga et al. 1999 | |
| Atelosteogenesis type II (DTDST, SLC26A2) | — | Lethal dysplasia | Hästbacka et al. 1996 | |
| Achondrogenesis type 1B (DTDST, SLC26A2) | — | Lethal dysplasia | Superti-Furga et al. 1996 | |
| SEMD Pakistani type (PAPS synthase 2) | — | SEMD | ul Haque et al. 1998 | |
| Brachymorph mouse (PAPS synthase 2) | — | Dome-shaped skull, shortened tail and limbs | Kurima et al. 1998; ul Haque et al. 1998 | |
| Brachyolmia, recessive (PAPS synthase 2 | — | Short trunk dysplasia | Miyake et al. 2012 | |
| SED Omani type (C6ST-1) | — | SED | Thiele et al. 2004 | |
| Chondrodysplasia, GPAPP type (IMPAD1) | — | Chondrodysplasia with joint dislocations | Vissers et al. 2011 | |
| Impaired G3 function | SEMD-ACAN | Possibly mild proportional short stature | SEMD | Tompson et al. 2009 |
| Familial OCD (ACAN) | OCD, short stature, OA | ? | Stattin et al. 2010 |
ACAN, aggrecan gene; C6ST, chondroitin-6-O-sulfotransferase; cmd, cartilage matrix deficiency; DTDST, diastrophic dysplasia sulfate transporter; GPAPP, Golgi-resident nucleotide phosphatase gene; IMPAD1, GPAPP gene; MED, multiple epiphyseal dysplasia; OA, osteoarthritis; OCD, osteochondritis dissecans; PAPS, 3′-phosphoadenosine 5′-phosphosulfate; SED, spondyloepiphyseal dysplasia; SEMD, spondyloepimetaphyseal dysplasia; SLC26A2, solute carrier family 26 (sulfate transporter), member 2; SLC35D1, solute carrier family 35 (UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter), member D1. For recessively inherited conditions, the lack of phenotype in heterozygous individuals is indicated by a dash.