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Table 1 Genetic and molecular findings in human aggrecanopathies and naturally occurring animal models

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

Gene mutation Exon Protein change Domain Molecular mechanism Phenotype Reference
c.272delA 3 Arg93Alafs*41 G1 Presumed haploinsufficiency Idiopathic short stature [15]
c.2026 + 1G > A 10 Not determined (but presumed exon skip) G2 1.Presumed truncated protein Idiopathic short stature [15]
2. Possible disruption to trafficking
c.3986dupC 12 Gly1330Trpfs*221 CS1 Presumed haploinsufficiency SED Kimberley type [13]
c.5391delG 12 Gly1797Glyfs*52 CS2 Presumed haploinsufficiency Dominant idiopathic short stature [22]
c.7064 T > C 14 Leu2355Pro G3 Presumed neomorphic Short stature, accelerated bone maturation, and early growth cessation [15]
c.6799G > A 15 Asp2267Asn G3 Presumed neomorphic Recessive SEMD, aggrecan type [12]
c.7249G > A 16 Val2303Met G3 Presumed neomorphic Dominant osteochondritis dissecans, short stature, and early-onset osteoarthritis [14, 17]
BD1 allele: 2266_2267insGGCA 11 Frame shift and introduction of PTC in exon 11 (amino acid position 914)   1. Null due to NMD of mRNA from mutant allele Bulldog dwarfism (Dexter Cattle) [11]
Homozygous animals are embryonically lethal; heterozygous animals have short-limbed dwarfism with variable penetrance
2. Functional null due to production of truncated protein
BD2 allele: −198C > T 1 Introduction of a novel start codon and translation of a 91 amino acid peptide with no resemblance to aggrecan; introduction of a PTC n/a
7 bp deletion leading to a PTC in exon 6. 5 Reduced mRNA levels in cmd/cmd (41 %) and cmd/wt (81 %) mice; truncated aggrecan molecule G1 Functional and/or transcriptional null allele Cmd (mouse) [2429]
Homozygous mice are perinatally lethal; heterozygous mice show age-related spinal degeneration
Large deletion 2–18 Unknown G1-G3 Presumed null allele Cmd-bc (mouse) [30]
Homozygous mice are perinatally lethal
Glu1513Ter 10 Truncated aggrecan precursor that is retained in the ER; reduced mRNA levels CS2 Presumed null allele Nanomelia (chicken) [9, 27, 29, 31, 33]
Homozygous chicks are embryonically lethal with shortened and malformed limbs
Unknown n/a Unknown Unknown Unknown CCI (rat) [35]
Homozygous rats have short-limbed dwarfism, delayed anterior fontanel closing and insufficient cartilage calcification
  1. Details of the five aggrecan mutations that have been identified in families with a diverse range of human skeletal dysplasia and the naturally occurring animal models that have previously been studied
  2. Key: NMD nonsense mediated degradation, PTC premature termination codon, G1 globular domain, G2 globular domain, CS chondroitin sulphate attachment domain, SED spondyloepiphyseal dysplasia, SEMD spondyloepimetaphyseal dysplasia, BD bull dog dwarfism, cmd cartilage matrix deficiency allele/mouse, wt wild type allele
  3. *Indicates at which position the new reading frame encounters a translation termination (stop) codon stop