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Novel Mutations Responsible for Autosomal Recessive Multisystem Pseudohypoaldosteronism and Sequence Variants in Epithelial Sodium Channel -, ß-, and -Subunit Genes

Department of Chemical Engineering and Biotechnology, The College of Judea and Samaria, Ariel 44837, Israel; Department of Pediatrics, Royal Free and University College Medical School, The Rayne Institute (R.J.T., R.M.G.), United Kingdom WC1E 6JJ; and Department of Pediatrics, Tel-Aviv University Sackler Medical School, E. Wolfson Hospital (A.H.), Holon, 58100, Israel

Address all correspondence and requests for reprints to: Dr. Aaron Hanukoglu, Department of Pediatrics, E. Wolfson Hospital, Holon, 58100 Israel. E-mail: . aaronh{at}science.co.il

Abstract

Multisystem pseudohypoaldosteronism (PHA), is a syndrome of unresponsiveness to aldosterone with autosomal recessive inheritance. Previously we showed that mutations in the epithelial sodium channel (ENaC) -, ß-, and -subunits are responsible for PHA. In this study we examined four independent probands with multisystem PHA, three of whom were born to consanguineous parents. In our search for mutations we also determined the complete coding sequences of each of the three genes encoding -, ß-, and -subunits in individuals representing different ethnic groups. Our analyses revealed the following homozygous mutations in three probands: 1) insertion of a T in exon 8 of the ENaC gene that causes a frameshift error at Tyr⁴⁴⁷ and leads to a premature stop codon at K459 in a Pakistani patient; 2) R508stop mutation in exon 11 of the ENaC gene in an Indian patient; and 3) a splice site mutation in intron 12 of the ß ENaC gene (1669 + 1 ga) in a Scottish patient. The parents were heterozygous for the latter two mutations. The second mutation was previously observed in an Iranian Jewish patient. Our sequencing of the -, ß-, and -coding sequences revealed some sequence variants, some of which may represent single nucleotide polymorphisms. The -subunit protein sequence was completely conserved in the six subjects examined. The homozygous mutations identified in the and ß ENaC genes should result in reduced or abolished ENaC activity in PHA patients, explaining the disease symptoms.

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