Table 1.

Genetic diseases with altered DCT function.

Disease	Affected gene	Affected protein	Mutation	Mendelian inheritance	Proposed mechanism
Gitelman syndrome	SLC12A3	NCC	Loss‐of‐function missense, nonsense, or frameshift‐introducing mutations in > 100 different positions along the protein, small deletions, mutations at donor and acceptor splice sites, etc.	Autosomal recessive	Impaired NCC activity due to impaired protein synthesis, increased cotransporter degradation, impaired trafficking to plasma membrane, impaired cotransporter function, etc.	Acuna et al (2011), Gamba (2005), Sabath et al (2004)
FHHt	WNK1	WNK1	Deletions in intron 1	Autosomal dominant	Ectopic L‐WNK1 expression in the DCT	Vidal‐Petiot et al (2013), Wilson et al (2001)
		WNK1	Missense mutations in the acidic domain	Autosomal dominant	Decreased KS‐WNK1 degradation in the DCT	Louis‐Dit‐Picard et al (2020)
	WNK4	WNK4	Missense mutations in the acidic domain	Autosomal dominant	Decreased WNK4 degradation in the DCT	Brooks et al (2012), Golbang et al (2005), Gong et al (2008), Shibata et al (2013), Wakabayashi et al (2013), Wilson et al (2001)
		WNK4	Missense mutations in the C‐terminal regulatory region: R1185C and K1169E	Autosomal dominant	Disruption of inhibitory domain that promotes increased WNK4 activity	Na et al (2012), Wilson et al (2001), Zhang et al (2011)
	KLHL3	KLHL3	Several missense mutations clustered in the BTB domain and specific regions of the kelch propeller domain	Autosomal dominant	Decreased WNK4 and KS‐WNK1 degradation in the DCT	Boyden et al (2012), Louis‐Dit‐Picard et al (2012), Susa et al (2014), Susa et al (2017)
		KLHL3	Several loss‐of‐function missense, nonsense, and splicing‐altering mutations	Autosomal recessive	Decreased WNK4 and KS‐WNK1 degradation in the DCT	Boyden et al (2012), Louis‐Dit‐Picard et al (2012), Sasaki et al (2017)
	CUL3	CUL3	Mutations that affect the splicing of exon 9 and result in an internal deletion of 57 amino acid residues in the protein	Autosomal dominant	Decreased WNK4 and KS‐WNK1 degradation in the DCT; impaired vascular relaxation through activation of RhoA‐ROCK pathway	Abdel Khalek et al (2019), Boyden et al (2012), Ferdaus et al (2017), Ostrosky‐Frid et al (2020)
SESAME / EAST syndrome	KCNJ10	Kir4.1	Loss‐of‐function missense or nonsense mutations	Autosomal recessive	Impaired function of Kir4.1/Kir5.1 heterotetramers in the DCT leading to decreased basolateral K+ conductance	Bockenhauer et al (2009), Scholl et al (2009), (Reichold et al (2010)