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Background <p>Aldosterone plays a critical role in sodium homeostasis by binding to the mineralocorticoid receptor promoting sodium retention. It increases the expression of epithelial sodium channels (ENaC) and sodium-potassium ATPases in the renal distal tubules and collecting ducts. Defects in aldosterone synthesis lead to hyponatremia, hyperkalemia, hyperreninemia, metabolic acidosis, and hypovolemia.</p> Patient <p>We present a 7-year-old boy with holoprosencephaly, dysmorphic features, and short stature presenting with persistent hyponatremia since birth and occasional hypokalemia and hyporeninemia. Initial whole exome sequencing (WES) identified a novel in-frame SHH variant, NM_000193.4:c.755_757del (p.Phe252del); possible aldosterone deficiency due to adrenocortical hypoplasia caused by the SHH variant did not fully explain the patient’s clinical presentation, prompting further investigation.</p> Results <p>Deep analysis of the WES data revealed a second variant of unknown significance in the SCNN1G gene affecting the γ-ENaC subunit, namely NM_001039.4.1904&#xa0;C &gt; T (p.Ala635Val), which was previously unreported in association with a clinical phenotype. Electrophysiological studies of the amiloride-sensitive current before and after trypsin exposure showed that the γ-ENaC-A635V mutation reduced the amiloride-sensitive sodium current by approximately 30%. The trypsin experiments suggested a lower channel open probability and a reduced inward sodium current through the ENaC.</p> Conclusions <p>These findings indicate that the A635 residue participates in channel function, with γ-Α635V leading to decreased sodium reabsorption. This case underscores the importance of reevaluating genetic data to understand complex clinical presentations and identifies a new potential pathogenic variant affecting sodium homeostasis. The case illustrates how genetic variants with contrasting effects on a physiological loop along with functional changes due to development and age may be hard to interpret.</p>

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Functional properties of the γ-ENaC-A635V mutation in a patient with severe hyponatremia

  • 期刊论文

  • 发表日期：

    2025年3月28日

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  • Marita Antoniadi,
  • Marc Bohnet,
  • Stephan Kellenberger,
  • Dimitra-Irinna Vitoratou,
  • Olga Fafoula,
  • Fani Mylona,
  • Stavroula Kostaridou,
  • Danai Palaiologou,
  • Anna Taliou,
  • Constantine A. Stratakis

摘要

Background

Aldosterone plays a critical role in sodium homeostasis by binding to the mineralocorticoid receptor promoting sodium retention. It increases the expression of epithelial sodium channels (ENaC) and sodium-potassium ATPases in the renal distal tubules and collecting ducts. Defects in aldosterone synthesis lead to hyponatremia, hyperkalemia, hyperreninemia, metabolic acidosis, and hypovolemia.

Patient

We present a 7-year-old boy with holoprosencephaly, dysmorphic features, and short stature presenting with persistent hyponatremia since birth and occasional hypokalemia and hyporeninemia. Initial whole exome sequencing (WES) identified a novel in-frame SHH variant, NM_000193.4:c.755_757del (p.Phe252del); possible aldosterone deficiency due to adrenocortical hypoplasia caused by the SHH variant did not fully explain the patient’s clinical presentation, prompting further investigation.

Results

Deep analysis of the WES data revealed a second variant of unknown significance in the SCNN1G gene affecting the γ-ENaC subunit, namely NM_001039.4.1904 C > T (p.Ala635Val), which was previously unreported in association with a clinical phenotype. Electrophysiological studies of the amiloride-sensitive current before and after trypsin exposure showed that the γ-ENaC-A635V mutation reduced the amiloride-sensitive sodium current by approximately 30%. The trypsin experiments suggested a lower channel open probability and a reduced inward sodium current through the ENaC.

Conclusions

These findings indicate that the A635 residue participates in channel function, with γ-Α635V leading to decreased sodium reabsorption. This case underscores the importance of reevaluating genetic data to understand complex clinical presentations and identifies a new potential pathogenic variant affecting sodium homeostasis. The case illustrates how genetic variants with contrasting effects on a physiological loop along with functional changes due to development and age may be hard to interpret.