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 | |
BD1 allele: 2266_2267insGGCA | 11 | Frame shift and introduction of PTC in exon 11 (amino acid position 914) | Â | 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 | |||
7Â bp deletion leading to a PTC in exon 6. | 5 | Reduced mRNA levels in cmd/cmd (41Â %) and cmd/wt (81Â %) mice; truncated aggrecan molecule | G1 | Functional and/or transcriptional null allele | Cmd (mouse) | |
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) | |
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 |