Table 1.

Disease mechanisms and potential therapeutic targets in selected GSDs resulting from antimorphic mutations in cartilage structural proteins.

Gene	Protein	Disease	In	Molecular mechanism	Cell and/or tissue mechanism	Target (s)	Treatment	Ref.
COL2A1	Type II collagen	Various type II collagenopathies (for details see legend)	AD	Various antimorphic missense mutations and small in-frame deletions	Some mutations cause ER stress, reduced chondrocyte proliferation and increased apoptosis Disrupted ECM organization	ER stress through pharmacological intervention. Mutant protein degradation by the proteasome or autophagy	TMAO	[11–13]
COL9A1	Type IX collagen	MED (EDM2, 3 & 6)	AD	Exon skipping and in-frame deletion in COL3 domain	Potential disruption to collagen fibril structure and cartilage ECM composition organization	No known target	None tested
COL9A2
COL9A3
COL10A1	Type X collagen	Metaphyseal chondrodysplasia, Schmid type	AD	Various antimorphic missense mutations and small in-frame deletions	ER stress, UPR and chondrocyte reprogramming Disrupted ECM organization	ER stress through pharmacological intervention. Mutant protein degradation by the proteasome or autophagy	None tested	[10,16,21]
COL11A1	Type XI collagen	OSMED	AR	Homozygous missense mutations	Some mutations may cause ER stress, reduced chondrocyte proliferation and increased apoptosis Disrupted ECM organization	ER stress through pharmacological intervention. Mutant protein degradation by the proteasome or autophagy	None tested
COL11A1		Stickler syndrome type 2	AD	Heterozygous missense mutations			None tested
COL11A1		Marshall	AD	Exon skip resulting in an in-frame deletion and missense mutations			None tested
COL11A2		Stickler syndrome type 3	AD	Exon skip resulting in an in-frame deletion			None tested
COL11A2		OSMED/WZS	AD	Heterozygous missense mutations			None tested
COL11A2		Fibrochondrogenesis 2	AR	Homozygous mutations predicted to result in-frame deletions in triple helix			None tested
COMP	COMP	Pseudoachondroplasia MED	AD	Various antimorphic missense mutations and small in-frame deletions	ER stress, reduced chondrocyte proliferation and increased/dysregulated apoptosis Disrupted ECM organization	ER and/or oxidative stress through pharmacological intervention. Mutant protein degradation by the proteasome or autophagy	Aspirin Lithium Valproate SPB	[18–20,26–29]
MATN3	Matrilin-3	MED (EDM5)	AD	Various antimorphic missense mutations and small in-frame deletions	ER stress, UPR, reduced chondrocyte proliferation and dysregulated apoptosis Disrupted ECM organization	ER stress through pharmacological intervention. Mutant protein degradation by the proteasome or autophagy	SPB	[17,22,23]
ACAN	Aggrecan	Idiopathic short stature	AD	L2355P antimorphic missense mutation	Mutant aggrecan appears to be secreted. Possible altered cartilage ECM composition though disrupted binding to ECM components via the aggrecan G3 domain	No known target	None tested
		Spondyloepimetaphyseal dysplasia	AR	D2267N antimorphic missense mutation
		Osteochondritis dissecans	AD	V2303M antimorphic missense mutation

Type II collagenopathies include: Achondrogenesis, type II or hypochondrogenesis (200610), avascular necrosis of the femoral head (608805), Czech dysplasia (609162), epiphyseal dysplasia, multiple, with myopia and deafness (132450), Kniest dysplasia (156550) Legg-Calve-Perthes disease (150600), osteoarthritis with mild chondrodysplasia (604864), otospondylomegaepiphyseal dysplasia (215150), platyspondylic skeletal dysplasia, Torrance type (151210), SED congenital (183900), SED, Namaqualand type, SMED Strudwick type (184250), spondyloperipheral dysplasia (271700).

AD: Autosomal dominant; AR: Autosomal recessive; COL: Collagenous domain; ECM: Extracellular matrix; ER: Endoplasmic reticulum; G3: Globular domain; GSDs: Genetic skeletal diseases; MED: Multiple epiphyseal dysplasia; SPB: Sodium phenylbutyrate; TMAO: Trimethylamine N-oxide; UPR: Unfolded protein response.