Table 1.

Hereditary human lymphedema conditions involving the vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR-3) signaling pathway.

GENE (protein)	Human condition (OMIM, alternative name)	Lymphedema phenotype	Reference for the initial linkage	Molecular etiology	Viable animal models
FLT4 (VEGFR-3)	Hereditary lymphedema type 1A (153100, Milroy disease)	Predominantly the lower extremities	Irrthum et al. (2000), Karkkainen et al. (2000)	Dominant negative inactivation of the intracellular kinase domain (Irrthum et al., 2000; Karkkainen et al., 2000)	Chy mice (inactivating Flt4 mutation) (Karkkainen et al., 2001b); VEGFR-3 inhibition (Mäkinen et al., 2001)
VEGFC (VEGF-C)	Hereditary lymphedema type 1D (615907, Milroy-like disease)		Gordon et al. (2013), Balboa-Beltran et al. (2014)	Secretion defect (Gordon et al., 2013; Villefranc et al., 2013)	Chy-3 mice (hemizygous Vegfc deletion) (Dellinger et al., 2007); conditional Vegfc ko mice (Nurmi et al., 2015)
CCBE1 (Collagen and calcium-binding EGF domain-containing protein 1)	Hennekam syndrome type 1 (235510)	Generalized	Alders et al. (2009)	A disintegrin and metalloproteinase with thrombospondin motifs 3 activation defect (Jeltsch et al., 2014; Roukens et al., 2015), localization defect (Jha et al., 2017)	Conditional Ccbe1 ko mice (Bui et al., 2016)
	Cholestasis–lymphedema syndrome (214900, Aagenaes syndrome)		Shah et al. (2013), Viveiros et al. (2017)
FAT4 (Protocadherin Fat4)	Hennekam syndrome type 2 (616006)		Alders et al. (2014)	Unknown molecular etiology	Vascular abnormalities were not reported for the full Fat4 ko mice (Saburi et al., 2008)
	Van Maldergem syndrome type 2 (615546)
ADAMTS3 (A disintegrin and metalloproteinase with thrombospondin motifs 3)	Hennekam syndrome type 3		Brouillard et al. (2017)	Secretion defect (Brouillard et al., 2017), localization defect (Jha et al., 2017)	Conditional Adamts3 ko mice (Bui et al., 2016)