Table 3.
Disease mechanisms in selected GSDs resulting from haploinsufficiency for cartilage structural proteins.
| Gene | Protein | Disease | In | Molecular mechanisms | Cell and/or tissue mechanism |
|---|---|---|---|---|---|
| COL2A1 | Type II collagen | Stickler syndrome type 1 | AD | Heterozygous nonsense mutations or out of frame deletions leading to frameshift | Presumed haploinsufficiency for type II collagen Potential antimorpic disruption to collagen fibril structure and cartilage organization |
| COL9A1 | Type IX collagen | Stickler syndrome type 4 | AR | Homozygous nonsense mutations | Presumed haploinsufficiency for type IX collagen Potential antimorpic disruption to collagen fibril structure and cartilage organization Possible ER stress associated with the degradation of excess collagen α(IX) chains |
| COL9A2 | Stickler syndrome type 5 | Homozygous for predicted frame shift mutations and a premature termination codon | |||
| COL9A3 | Stickler syndrome type 6 | Homozygous out of frame deletion leading to frameshift and a premature termination codon | |||
| COL10A1 | Type IX collagen | Metaphyseal chondrodysplasia, Schmid type | AD | Heterozygous nonsense mutations or out of frame deletions leading to frameshift and a premature termination codon | Haploinsufficiency for type X collagen due to NMD of mRNA from mutant allele Possible ER stress associated with NMD Potential disruption to cartilage structural organization |
| COL11A1 | Type XI collagen |
Fibrochondrogenesis 1 | AR | Compound heterozygosity for a loss-of-function mutation and an antimorphic missense mutation (glycine substitution) | Haploinsufficiency of α2(XI) collagen chains due to NMD of mRNA from mutant allele Possible ER stress resulting in a fibroblastic appearance of the chondrocytes Antimorpic disruption to collagen fibril structure producing a fibrous ECM |
| COL11A2 | OSMED/WZS | AR | Homozygous for nonsense mutations Absence of α2(XI) collagen chains due to NMD of mRNA from mutant alleles |
Potential antimorpic disruption to collagen fibril structure and cartilage organization Possible ER stress associated with the degradation of excess α1(XI) collagen chains |
|
| ACAN | Aggrecan | Idiopathic short stature | AD | Predicted frame shift mutations leading to a premature termination codon | Presumed haploinsufficiency for aggrecan due to NMD of mRNA from mutant allele Potential antimorpic disruption to cartilage structure and tissue organization |
| SED Kimberley | AD |
AD: Autosomal dominant; AR: Autosomal recessive; ER: Endoplasmic reticulum; ECM: Extracellular matrix; GSDs: Genetic skeletal diseases; NMD: Nonsense-mediated degradation.