A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population

Abstract

Context: Pseudohypoaldosteronism (PHA) is a condition in which serum aldosterone level is normal or elevated but its action is deficient.

Objective: This study describes the molecular genetics of PHA 1b in the highly consanguineous population of 2 Arabian Gulf countries, Saudi Arabia and Oman.

Methods: This study enrolled 22 patients from 13 unrelated families (2 families with 5 patients from Oman and 11 families with 17 patients from Saudi Arabia). All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension. We isolated DNA from peripheral blood and PCR-sequenced all exons and exon-intron boundaries of SCNN1A and, if negative, SCNN1B and SCNN1G using the Dideoxy Chain termination method.

Results: We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G. All of these mutations were novel except one. SCNN1A mutations were: c.1496A>G, p.Q499R (novel) in 1 patient; c.1453C>T, p.Q485X (novel) in 1 patient; c.1322_1322delA, p.N441Tfs*41 (novel) in 2 patients of 1 family; c.876 + 2 delGAGT (novel) in 3 patients of 1 family; c.203_204 delTC, p.I68Tfs*76 (a known mutation) in 8 patients of 5 families; and whole SCNN1A gene deletion (novel) in 2 patients of 2 families. In addition, a nonsense SCNN1B mutation c.1694C>A, p.S565X (novel) was found in 3 siblings from 1 Omani family, and an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family.

Conclusion: We characterized a unique genotype of PHA 1b with several novel gene structure-disrupting mutations in SCNN1A, SCNN1B, and SCNN1G in a highly consanguineous population.

Keywords: ENaC; PHA; SCNN1A; SCNN1B; SCNN1G; pseudohypoaldosteronism; sodium epithelial channel.

Figure 1.

The sequence chromatograms showing different SCNN1A mutations found in this study. A) SCNN1A: a is a missense mutation found in Family A; b is a nonsense mutation found in Family B; c is a deletion mutation found in Family C; d is a splice-site mutation found in Family D; e is a deletion mutation found in Families E, F, G, H, I. B), f is an SCNN1B nonsense mutation in Family L; and C), g is an SCNN1G deletion mutation in Family M.

Figure 2.

Gel electrophoresis of PCR of exons 1-12 of SCNN1A showing successful amplification of the normal control but failure to amplify any of exons 1-12 in patients J1 or K1. A simultaneous PCR using the same master mix for SCNN1B successfully amplified all exons in the normal control, as well as patients J1 and K1. This indicates that SCNN1A was deleted in patients J1 and K1. This experiment was repeated 3 times.