Table 2.

Disease mechanisms and potential therapeutic targets in selected GSDs resulting from a disruption to protein trafficking in chondrocytes.

Gene	Protein	Disease	In	Molecular mechanisms	Cell and/or tissue mechanism	Target(s)	Ref.
DDR2	Discordin domain receptor 2	Spondyo-meta-epiphyseal dysplasia with short limbs	AR	Missense and exon skipping mutations	Retention within the ER, loss of collagen-binding activity and signalling. ER stress, reduced chondrocyte proliferation	Modulation of the secretory pathway. Restoration of normal rates of secretory protein synthesis and secretion	[30–32]
TRAPPC2	Trafficking Protein Particle Complex 2	Spondyloepiphyseal dysplasia Tarda	XR	Various antimorphic and loss of function (nonsense) mutations	Defect in the trafficking and secretion cartilage structural proteins		[33–35]
TRIP11	Thyroid Hormone Receptor Interactor 11	Achondrogenesis type I	AR	Homozygous or compound heterozygous for loss-of-function mutations	Disrupted golgi structure, ER stress, abnormal chondrocyte differentiation and increased apoptosis		[39]
SEC23A	Protein transport proteins	Cranio-lenticulo-sutural dysplasia	AR	Homozygous missense mutation causes loss of protein function	Accumulation of proteins, in particular fibrillar collagens and matrilins, within the ER of relevant cell types		[36]
Sec23a		Zebrafish crusher mutant	AR	Homozygous nonsense mutation causes loss of protein function			[37]
Sec24d		Zebrafish bulldog mutant	AR	Loss of protein function			[38]

AD: Autosomal dominant; AR: Autosomal recessive; ER: Endoplasmic reticulum; GSDs: Genetic skeletal diseases; XR: X-linked recessive.