Pseudohypoaldosteronism, Type Iie

A number sign (#) is used with this entry because pseudohypoaldosteronism type IIE (PHA2E) is caused by heterozygous mutation in the CUL3 gene (603136) on chromosome 2q36.

For a phenotypic description and a discussion of genetic heterogeneity of pseudohypoaldosteronism type II, see PHA2A (145260).

Clinical Features

Boyden et al. (2012) studied a cohort of 52 PHAII kindreds, including 126 affected subjects with renal hyperkalemia and otherwise normal renal function; hypertension and acidosis were present in 71% and 82%, respectively. They detected 21 affected individuals from 17 kindreds with mutation in the CUL3 gene. The mean age at diagnosis or referral was 9 +/- 6 years, mean potassium was 7.5 +/- 0.9, and mean bicarbonate was 15.5 +/- 2.0. Hypertension was present in 94% of patients at or before 18 years of age. The CUL3 mutation patients had by far the most severe manifestations of PHAII compared to patients with other mutations.

Clinical Management

Thiazide diuretics correct abnormalities in virtually all PHAII subjects (Boyden et al., 2012).

Molecular Genetics

After identifying mutations in the KLHL3 gene (605775) in kindreds with PHAII (see 614495), Boyden et al. (2012) considered CUL3, the presumed functional partner of KLHL3, as a candidate. Sequencing CUL3 in 21 index patients revealed 17 with novel heterozygous CUL3 mutations. Eight of the 17 were de novo mutations. Boyden et al. (2012) observed that the CUL3 mutations identified in their cohort all clustered in sites implicated in splicing of exon 9, including the intron 8 splice acceptor (n = 4), the intron 9 splice donor (n = 5), the putative intron 8 splice branch site (n = 5), and a putative splice enhancer in exon 9 (n = 3, within a TTGGA(T/A)) splice enhancer consensus sequence.

Genotype/Phenotype Correlations

Boyden et al. (2012) observed that families with PHAII due to mutation in the WNK1 gene (PHA2C; 614492) are significantly less severely affected than those with mutation in the WNK4 gene (PHA2B; 614491) or dominant or recessive mutation in the KLHL3 gene (605775; PHA2D, 614495), and all are less severely affected than those with dominant mutation in the CUL3 gene (PHA2E).