Table 4.

Disease mechanisms and potential therapeutic targets in selected GSDs resulting from constitutively activating mutations.

Gene	Protein	Disease	In	Molecular Mechanisms	Cell and/or tissue mechanism	Target(s)	Treatment	Ref.
FGFR3	Fibroblast growth factor receptor 3	Achondroplasia Hypochondroplasia Thanatophoric dysplasia Thanatophoric dysplasia	AD	Missense gain of function missense mutations causing constitutive activation of FGFR3	Reduced chondrocyte proliferation with disrupted growth plate architecture	Pharmacological inhibition of MEK-ERK signalling and modulations of MAPK pathway	BMN111 Statins Meclizine	[92–98]
PTH1R	Parathyroid hormone 1 receptor	Metaphyseal chondrodysplasia, Jansen type	AD	Missense mutations causing activation of the cAMP pathway	Reduced chondrocyte proliferation, with premature maturation of chondrocytes and accelerated bone formation	Pharmacological modulations of the PTH-PTHrP receptor pathway	GSK2193874 HC-067047	[80]
GNAS1	Guanine nucleotide binding protein, alpha stimulating	Fibrous dysplasia		Activating missense mutations which renders the gene functionally constitutive	Abnormal changes in cell shape and collagen structure	The constitutively active Gsα protein and downstream effectors	Bisphosphonate	[84,103]
TRPV4	Transient receptor potential cation channel subfamily V member 4	Brachyolmia type 3 SMD Kozlowski type Metatrophic dysplasia	AD	Missense gain of function mutations causing increased constitutive current before agonist application. Increased intracellular calcium ion concentration and activity	Abnormally thick cartilage with nodular proliferation. Abnormal chondrogenesis and abnormal differentiation of mesenchymal progenitors as well as lack of normal columns of chondrocytes	Blocking the calcium-permeable TRPV4 channel	None tested	[82,85,99–102]
ACVR1/ALK2	Activin receptor A, type I/Activin-like kinase 2	Fibrodysplasia ossificans progressiva	AD	Heterozygous activating mutations due to allosteric destabilization of an inactive receptor conformation and therefore a loss of autoinhibition	Formation of a second skeleton of heterotopic bone including congenital malformations of the great toes and progressive heterotopic endochondral ossification	BMP signalling pathway:- Blocking activity of the mutant receptor Blocking inflammatory Triggers Blocking Progenitor Cells	Palovarotene in Phase II clinical trails	[87,88]

AD: Autosomal dominant; AR: Autosomal recessive; BMP: Bone morphogenetic protein; GSDs: Genetic skeletal diseases; SMD: Spondylometaphyseal dysplasia.