Pseudohypoaldosteronism, Type Iid

A number sign (#) is used with this entry because pseudohypoaldosteronism type IID (PHA2D) can be caused by heterozygous, homozygous, or compound heterozygous mutation in the KLHL3 gene (605775) on chromosome 5q31.

Description

Familial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (summary by Louis-Dit-Picard et al., 2012).

Genetic Heterogeneity of Type II Pseudohypoaldosteronism

For a discussion of genetic heterogeneity of type II pseudohypoaldosteronism, 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. Among these 52 kindreds, 8 kindreds including 14 individuals carried recessive mutations in KLHL3, and 16 kindreds including 40 individuals carried dominant mutations. The phenotype of patients carrying either type of mutation was similar. The mean age at diagnosis or referral among patients with recessive mutations was 26 +/- 14 years. They had a mean potassium at time of diagnosis of 6.8 +/- 0.5; mean bicarbonate was 17.6 +/- 1.5; and only 14% had developed hypertension by 18 years of age. Among the patients with dominant mutations, mean age at diagnosis or referral was 24 +/- 18 years, mean potassium 6.2 +/- 0.6 mM, and mean bicarbonate 17.2 +/- 2.5; 17% had hypertension diagnosed by age 18 years.

Clinical Management

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

Molecular Genetics

Boyden et al. (2012) performed exome sequencing of 11 unrelated PHAII index cases without WNK mutations and identified novel KLHL3 mutations comprising 5 alleles in 3 kindreds, all of which cosegregated with the trait. Boyden et al. (2012) identified 1 kindred in which affected members were homozygous for a nonsense mutation (605775.0001), 1 in which affected members are compound heterozygous for 2 missense mutations (605775.0002, 605775.0003), and 1 segregating a heterozygous missense mutation (605775.0004). As a confirmation of significance, Fisher exact test was used to compare the prevalence of novel protein-altering variants in all genes in PHAII cases versus 699 control exomes. The KLHL3 gene showed a burden of mutation that surpassed genomewide significance (P = 1.1 x 10(-8)). The KLHL3 gene was sequenced in all PHAII index cases, and novel mutations were identified in 24. Nearly all were at positions conserved among orthologs. Sixteen kindreds had heterozygous mutations that cosegregated with the trait under a dominant model (lod score = 6.9, less than -2 under other models). In contrast, 8 index cases inherited mutations in both KLHL3 alleles. In these kindreds, affected members were confined to sibs of index cases who inherited the same 2 mutations, whereas unaffected relatives inherited zero or 1 mutation (lod score 4.3 for a recessive model, less than -2 for other models). This was the first report of recessive transmission for PHAII.

Boyden et al. (2012) observed that, consistent with 2 modes of transmission, subjects with dominant KLHL3 mutations had significantly higher serum potassium levels (6.2 +/- 0.6 mM) than heterozygotes for recessive mutations (4.8 +/- 0.6 mM) (P less than 10(-4), Student's t-test; normal range 3.5-5.0 mM). Boyden et al. (2012) concluded that PHAII can be caused by either recessive or dominant KLHL3 mutations, and inferred that mutations in dominant kindreds are probably dominant-negative because they phenocopy the features of recessive disease. While recessive KLHL3 mutations were distributed throughout the encoded protein, dominant KLHL3 mutations showed marked clustering. Nine of 16 dominant mutations altered 1 of the last 4 amino acids of the 6 'd-a' loops that connect the outermost (d) beta-strand of 1 kelch propeller blade to the innermost (a) beta-strand of the next blade. Two others were in 'b-c' loops. These dominant PHAH mutations lay near the hub of the propeller at or near sites implicated in substrate binding in paralogs. Three other dominant mutations clustered within the BTB domain, at or near sites implicated in cullin binding in paralogs. Boyden et al. (2012) inferred that dominant mutations in KLHL3 probably impair binding either to specific substrates or to CUL3.

In a 3-generation French family with hyperkalemic hypertension, Louis-Dit-Picard et al. (2012) performed whole-exome sequencing in 1 unaffected and 3 affected family members and identified a heterozygous missense mutation in the KLHL3 gene (R528H; 605775.0004) that segregated with disease. A larger, 4-generation French family with a milder phenotype, in which only 3 of 14 affected individuals with hyperkalemia also had hypertension, showed linkage to chromosome 5q31 and was found to harbor a different heterozygous missense mutation in KLHL3 (A398V; 605775.0010) that segregated with disease. Analysis of KLHL3 in 43 probands with FHHT revealed 8 families in which a heterozygous missense mutation segregated with disease (see, e.g., 605775.0003, 605775.0008, and 605775.0011), as well as 4 consanguineous cases in which a homozygous missense mutation was found (see, e.g., 605775.0012). On average, the recessive cases were diagnosed at an earlier age (2.5 months to 17 years) than those with heterozygous mutations (15 to 56 years) and had a more severe phenotype. Screening of the KLHL3 gene in 1,232 individuals with essential hypertension (see 145000) revealed only 1 deleterious mutation in a hypertensive patient with mild hyperkalemia; Louis-Dit-Picard et al. (2012) concluded that missense mutations causing hyperkalemic hypertension are rare in the general hypertensive population of European descent. No KLHL3 mutations were found in 800 normotensive individuals.

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 WNK4 (PHA2B; 614491) or dominant or recessive mutation in the KLHL3 gene (PHA2D), and all are less severely affected than those with dominant mutations in the CUL3 gene (603136; PHA2E, 614496).

Animal Model

Using transgenic mice, Susa et al. (2014) found that heterozygous expression of human KLHL3 with the arg528-to-his (R528H; 605775.0004) mutation caused a high salt-dependent elevation in systolic blood pressure compared with control mice or KLHL3(R528H/+) mice on a low-salt diet. Transgenic KLHL3(R528H/+) mice also showed hyperkalemia and metabolic acidosis under both low- and high-salt conditions. Homozygous KLHL3(R528H/R528H) mice showed similar salt-sensitive hypertension, hyperkalemia, and metabolic acidosis. Susa et al. (2014) concluded that the KLHL3(R528H/+) mouse is a model of PHA2D. KLHL3(R528H/+) mice had elevated renal expression of the kinases Wnk1 (605232) and Wnk4 (601844) in distal convoluted tubules, resulting in increased phosphorylation of the Wnk targets Osr1 (OXSR1; 604046) and Spak (STK39; 607648) and of the sodium-chloride channel Ncc (SLC12A3; 600968). Susa et al. (2014) proposed that the R528H mutation interferes with binding of KLHL3 to WNK1 and WNK4, impairing ubiquitination and degradation of the kinases and resulting in activation of a phosphorylation cascade that elevates activity of sodium channels, such as ENaC (see 600228), and sodium-chloride channels, such as NCC, at the distal convoluted tubule.