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

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) alpha-, beta-, and gamma-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 alpha-, beta-, and gamma-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 alpha ENaC gene that causes a frameshift error at Tyr(447) and leads to a premature stop codon at K459 in a Pakistani patient; 2) R508stop mutation in exon 11 of the alpha ENaC gene in an Indian patient; and 3) a splice site mutation in intron 12 of the beta ENaC gene (1669 + 1 g-->a) 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 alpha-, beta-, and gamma-coding sequences revealed some sequence variants, some of which may represent single nucleotide polymorphisms. The gamma-subunit protein sequence was completely conserved in the six subjects examined. The homozygous mutations identified in the alpha and beta ENaC genes should result in reduced or abolished ENaC activity in PHA patients, explaining the disease symptoms.

Could a defective epithelial sodium channel lead to bronchiectasis

“…Four of the missense mutations were detected in patients with functional abnormalities suggesting impaired sodium transport in the sweat glands or in the nasal epithelium : two variants (p.Pro369Thr, p.Asn288Ser in ENaCβ) were detected in this study for the first time and the other two (p.Ser82Cys and p.Gly183Ser) have been described before [ 13 ]. These variants have not been previously found in normal subjects in several studies [ 22 - 24 ] and were not detected in our ethnically-matched control group and in a "control" population of 56 cystic fibrosis patients with two pathogenic CFTR mutations [ 17 ]. They are therefore unlikely to be common polymorphisms.…”

Functional Polymorphism in the Carboxyl Terminus of the α-Subunit of the Human Epithelial Sodium Channel

“…Na ϩ channel gain-of-function mutations have been identified in patients with Liddle's syndrome, a disorder characterized by volume expansion, hypokalemia, and hypertension (10,11). ENaC loss-of-function mutations have been identified in patients with type I pseudohypoaldosteronism, a disorder characterized by volume depletion, hypotension, and hyperkalemia (12,13). Some common human ENaC polymorphisms may segregate with blood pressure (i.e.…”

Upregulation of Mineralocorticoid Receptor Contributes to Development of Salt-Sensitive Hypertension after Ischemia–Reperfusion Injury in Rats

“…The ENaC plays an important role in maintaining sodium homeostasis and body-fluid volume, but an excessive uptake of sodium contributes to the progression of salt-sensitive hypertension [ 46 , 47 , 48 ]. Additionally, the activation of the ENaC causes hypertension in some hereditary diseases, such as pseudohypoaldosteronism type 1 and Liddle syndrome [ 49 , 50 , 51 ]. Among the three components of the ENaC, γ-ENaC expression increased in IRI rats with salt overload or aldosterone infusion and was reduced by esaxerenone treatment.…”