SCNN1A – Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 (PHA1) is a rare congenital disorder characterized by renal and multi-organ unresponsiveness to aldosterone, resulting in severe salt wasting, hyperkalaemia, metabolic acidosis, and failure to thrive. The systemic autosomal recessive (AR) form arises from biallelic loss-of-function mutations in the epithelial sodium channel (ENaC) subunit genes, notably SCNN1A which encodes the α-subunit of ENaC.

Initial homozygosity mapping in 11 consanguineous families established linkage of AR-PHA1 to chromosome 12p13.1-pter encompassing SCNN1A, achieving a maximum LOD score of 9.9 (PMID:8824886).

To date, over 45 distinct pathogenic SCNN1A variants have been reported in more than 100 affected individuals, including homozygous missense (c.727T>C (p.Ser243Pro)) (PMID:21653223), nonsense (c.398G>A (p.Cys133Tyr)) (PMID:12376807), and frameshift (c.729_730del (p.Val245GlyfsTer65)) (PMID:33829730) alleles. Segregation analyses across multiple pedigrees confirm autosomal recessive inheritance with full concordance between homozygosity and disease manifestation.

Clinically, homozygous SCNN1A mutations present in the neonatal period with profound hyponatraemia (HP:0002902), hyperkalaemia (HP:0002153), metabolic acidosis (HP:0001942), and failure to thrive (HP:0001508). Heterozygous carriers exhibit subclinical salt-losing features, such as elevated sweat sodium and chloride concentrations, without overt hormonal disturbances (PMID:18547339).

Functional studies in Xenopus laevis oocytes demonstrate markedly reduced ENaC currents for p.Ser243Pro (~20% reduction) (PMID:21653223), a dominant-negative effect of p.Ser562Pro (PMID:18547339), and an 83% activity reduction plus decreased protein expression for p.Phe226Cys correlating with a mild, transient phenotype (PMID:37134141).

Collectively, the extensive genetic linkage, segregation, and functional data establish a definitive gene–disease association between SCNN1A and systemic pseudohypoaldosteronism type 1. Early molecular diagnosis enables tailored sodium supplementation and electrolyte management, significantly improving neonatal outcomes.

References

• Human molecular genetics • 1996 • Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping. PMID:8824886
• American journal of physiology. Endocrinology and metabolism • 2011 • A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1. PMID:21653223
• Pediatric nephrology (Berlin, Germany) • 2002 • A novel mutation of the epithelial Na+ channel causes type 1 pseudohypoaldosteronism. PMID:12376807
• Journal of clinical research in pediatric endocrinology • 2022 • A Novel SCNN1A Variation in a Patient with Autosomal-recessive Pseudohypoaldosteronism Type 1 PMID:33829730
• Clinical endocrinology • 2009 • Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the alpha subunit of the epithelial sodium channel. PMID:18547339
• American journal of physiology. Endocrinology and metabolism • 2023 • A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene. PMID:37134141

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