Table 1.

Monogenic disorders that have identified key skeletal genes in bone remodelling.

	Disease	Clinical features	Gene	Mechanism	Reference
Reduced bone mass	Osteoporosis- pseudoglioma syndrome (OPPGS)	Reduced bone mass and blindness	LRP5	Loss-of-function mutations disrupt Wnt signalling and reduce osteoblastic bone formation.	(Gong et al. 2001)
	Osteogenesis imperfecta	Increased bone fragility; blue sclerae in some types	COL1A1, COL1A2, CRTAP, LEPRE, PPIB	Loss-of-function mutations in collagen and collagen- processing proteins cause abnormal osteoid matrix, thereby impairing normal bone formation.	(Baldridge et al. 2008; Sykes et al. 1986; van Dijk et al. 2009)
	Juvenile-onset Paget disease	Short stature, fractures, skull enlargement, progressive deafness	TNFRSF11B (OPG)	Loss-of-function mutations disrupt inhibition of RANKL by osteoprotegerin, causing increased osteoclastic resorption of bone.	(Chong et al. 2003)
	X-linked osteoporosis	Juvenile-onset fractures in males	PLS3	Loss-of-function mutations affect Plastin-3, an actin-binding protein. Mechanism osteoporosis is unknown.	(van Dijk et al. 2013)
Increased bone mass	Osteopetrosis	Increased bone mass with fractures	TNFRSF11A (RANK), TNFSF11 (RANKL), CLCN7, TCIRG1, OSTM1	Loss-of-function mutations affecting osteoclast differentiation and function cause reduced bone resorption.	(Frattini et al. 2000; Guerrini et al. 2008; Kornak et al. 2001; Pangrazio et al. 2006; Sobacchi et al. 2007)
	Sclerosteosis and Van Buchem disease	Increased bone mass, syndactyly, entrapment neuropathies	SOST	Loss-of-function mutations affect inhibition of Wnt signalling by sclerostin, causing increased osteoblastic bone formation.	(Balemans et al. 2001)
	Autosomal dominant high bone mass	Increased bone density, entrapment neuropathies, square jaw and torus palatinus	LRP5	Gain-of-function mutation in Wnt co-receptor causes increased osteoblastic bone formation.	(Boyden et al. 2002)