ORPHA: 757, 88939;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.2 | Pseudohypoaldosteronism, type IIB | 614491 | Autosomal dominant | 3 | WNK4 | 601844 |
A number sign (#) is used with this entry because pseudohypoaldosteronism type IIB (PHA2B) is caused by heterozygous mutation in the WNK4 gene (601844) on chromosome 17q21.
For a phenotypic description and a discussion of genetic heterogeneity of pseudohypoaldosteronism type II, see PHA2A (145260).
Farfel et al. (1978, 1978) described an Ashkenazi Jewish family in which some members had hyperkalemia (6-7 mEq/L) evident in childhood and hypertension that developed later in life. The patients had mild acidosis of the proximal renal tubular acidosis type. Chlorothiazide administration promptly corrected all features. The syndrome affected 7 members of 3 generations with instances of male-to-male transmission, thus indicating autosomal dominant inheritance. Investigations showed normal renal and adrenal function. Aldosterone concentrations were normal, but probably inappropriately low for the level of hyperkalemia. Renin was low. A low-salt diet reduced blood pressure and urinary sodium (in contrast to the salt loss that occurs in pseudohypoaldosteronism) but serum potassium did not change. Aldosterone administration caused the expected decrease in urinary sodium but no increase in urinary potassium, supporting a mechanism of resistance to aldosterone regarding potassium but not sodium transport. Infusion of insulin produced hypoglycemia but no substantial reduction in serum potassium in 3 patients studied. Farfel et al. (1978) suggested the existence of a generalized cellular defect in transmembrane potassium transport (in which the kidneys, of course, participate) rather than an isolated renal tubular abnormality.
In the family reported by Lee et al. (1979) and Lee and Morgan (1980), 2 generations were affected.
Thiazide diuretics correct abnormalities in virtually all PHAII subjects (Boyden et al., 2012).
By linkage analysis, Mansfield et al. (1997) demonstrated linkage of PHAII both to 1q31-q42 (PHA2A) and 17p11-q21 (PHA2B). Analysis of both chromosome regions together yielded a lod score of 8.1 for linkage of all families to either chromosome 1 (68% of families) or chromosome 17 (32% of families), with odds of 130 million:1 favoring linkage to 2 loci over the null hypothesis of no linkage. The chromosome 17 locus overlapped with the syntenic segment of rat chromosome 10 that contains a blood pressure quantitative trait locus (QTL).
Wilson et al. (2001) identified the WNK4 gene (601844) between D17S250 and D17S579, within the minimum genetic interval containing the PHA2B locus. They identified 4 missense mutations in PHAII kindreds that had previously been linked to chromosome 17.
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 5 kindreds with mutations in WNK4. There were 15 affected individuals diagnosed or referred at age 28 +/- 18 years with a mean potassium of 6.4 +/- 0.7; a mean bicarbonate 20.8 +/- 2.3, and only 10% had hypertension diagnosed at an age of less than or equal to 18 years.
Exclusion Studies
Mansfield et al. (1997) analyzed all exons of the AE1 gene (109270), which lies in the chromosome 17 region to which the PHA2B locus was assigned and encodes an ion exchanger, by SSCP in 15 PHAII index cases. They identified no novel variants altering the encoded protein.
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) or dominant or recessive mutation in the KLHL3 gene (PHA2D), 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]
Farfel, Z., Iaina, A., Levi, J., Gafni, J. Proximal renal tubular acidosis: association with familial normaldosteronemic hyperpotassemia and hypertension. Arch. Intern. Med. 138: 1837-1840, 1978. [PubMed: 718349] [Full Text: https://doi.org/10.1001/archinte.138.12.1837]
Farfel, Z., Iaina, A., Rosenthal, T., Waks, U., Shibolet, S., Gafni, J. Familial hyperpotassemia and hypertension accompanied by normal plasma aldosterone levels: possible hereditary cell membrane defect. Arch. Intern. Med. 138: 1828-1832, 1978. [PubMed: 718348]
Farfel, Z., Rosenthal, T., Shibolet, S., Iaina, A., Gafni, J. Familial hyperkalemia and hypertension. Harefuah 90: 468-470, 1976. [PubMed: 964728]
Lee, M. R., Ball, S. G., Thomas, T. H., Morgan, D. B. Hypertension and hyperkalaemia responding to bendrofluazide. Quart. J. Med. 48: 245-258, 1979. [PubMed: 504550]
Lee, M. R., Morgan, D. B. Familial hyperkalaemia responsive to benzothiadiazine diuretic. (Letter) Lancet 315: 879 only, 1980. Note: Originally Volume I. [PubMed: 6103235] [Full Text: https://doi.org/10.1016/s0140-6736(80)91378-1]
Mansfield, T. A., Simon, D. B., Farfel, Z., Bia, M., Tucci, J. R., Lebel, M., Gutkin, M., Vialettes, B., Christofilis, M. A., Kauppinen-Makelin, R., Mayan, H., Risch, N., Lifton, R. P. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21. Nature Genet. 16: 202-205, 1997. [PubMed: 9171836] [Full Text: https://doi.org/10.1038/ng0697-202]
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]