ORPHA: 757, 88940;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.33 | Pseudohypoaldosteronism, type IIC | 614492 | Autosomal dominant | 3 | WNK1 | 605232 |
A number sign (#) is used with this entry because pseudohypoaldosteronism type IIC (PHA2C) is caused by heterozygous mutation in the WNK1 gene (605232) on chromosome 12p13.
For a phenotypic description and a discussion of genetic heterogeneity of PHAII, see PHA2A (145260).
Disse-Nicodeme et al. (2000) analyzed a large French pedigree in which 12 affected members over 3 generations confirmed autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range, 5.2-6.2 mmol/liter), hyperchloremia (range, 100-109 mmol/liter), normal plasma creatinine, and low renin (179820) levels.
Wilson et al. (2001) studied a new PHAII kindred that included 10 living members with typical features of PHAII, including hypertension, hyperkalemia (mean serum potassium, 6.2 mM), normal glomerular filtration rate, suppressed plasma renin activity, normal or elevated aldosterone levels, hyperchloremia (mean serum chloride, 112 mM), and reduced bicarbonate (mean serum bicarbonate, 17.5 mM). These features were absent in unaffected kindred members, and inheritance of the trait was consistent with autosomal dominant transmission with high penetrance.
In a 3-generation French pedigree with 12 affected members with PHAII, Disse-Nicodeme et al. (2000) excluded genetic linkage for the 2 previously mapped PHAII loci as well as for the thiazide-sensitive sodium-chloride cotransporter gene (SLC12A3; 600968) on chromosome 16q. A genomewide screen using 383 microsatellite markers showed strong linkage to 12p13 (PHA2C). Haplotype analysis using 10 additional polymorphic markers led to a minimal 13-cM interval. Analysis of 2 obvious candidate genes, SCNN1A (600228) and GNB3 (139130), located within the interval showed no deleterious mutation.
Wilson et al. (2001) performed genomic sequence analysis of linkage in a 3-generation PHAII kindred, which demonstrated complete linkage of the phenotype to the most telomeric 2-cM segment of chromosome 12p, with a multipoint lod score of 5.07.
Wilson et al. (2001) found that members of a family with PHAII carried a deletion in the interval between D12S341 and D12S91. Further evaluation indicated that affected family members had a heterozygous 41-kb deletion within intron 1 of the WNK1 gene (605232.0001). Both deletion endpoints occur within Alu repetitive elements. Wilson et al. (2001) also identified a deletion in the WNK1 gene (605232.0002) in the family reported by Disse-Nicodeme et al. (2000).
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. The authors identified 2 kindreds with PHAII caused by WNK1 mutation. There were 23 affected individuals in those 2 kindreds. Mean age at diagnosis was 36 +/- 20 years with a mean potassium of 5.8 +/- 0.8 and a mean bicarbonate 22.4 +/- 4.6, and only 13% developed hypertension by 18 years of age.
Boyden et al. (2012) observed that families with PHAII due to mutation in the WNK1 gene (PHA2C) are significantly less severely affected than those with mutation in WNK4 (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 (603136; PHA2E, 614496).
Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R., Mane, S. M., Colussi, G., Lebel, M., Gordon, R. D., and 34 others. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482: 98-102, 2012. [PubMed: 22266938] [Full Text: https://doi.org/10.1038/nature10814]
Disse-Nicodeme, S., Achard, J.-M., Desitter, I., Houot, A.-M., Fournier, A., Corvol, P., Jeunemaitre, X. A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Am. J. Hum. Genet. 67: 302-310, 2000. [PubMed: 10869238] [Full Text: https://doi.org/10.1086/303020]
Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J.-M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P. Human hypertension caused by mutations in WNK kinases. Science 293: 1107-1112, 2001. [PubMed: 11498583] [Full Text: https://doi.org/10.1126/science.1062844]