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Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia

Naoko Amano1,2, Satoshi Narumi1,3, Katsuya Aizu4

  • 1Department of Pediatrics, Keio University School of Medicine, Tokyo, 160-8582, Japan.

The Journal of Clinical Endocrinology and Metabolism
|October 25, 2023
PubMed
Abstract

Insights

Genetic deletions in ZNRF3 exon 2 cause congenital adrenal hypoplasia by disrupting Wnt/β-catenin signaling. This study identifies a novel genetic cause for primary adrenal insufficiency in children.

Area of Science:

  • Endocrinology
  • Genetics
  • Molecular Biology

Background:

  • Primary adrenal insufficiency (PAI) is a critical condition where the adrenal cortex fails to produce adequate steroid hormones.
  • ZNRF3 acts as a negative regulator of Wnt/β-catenin signaling, while RSPO1 enhances it by removing ZNRF3.

Purpose of the Study:

  • To investigate a new genetic cause of PAI.
  • To explore the role of ZNRF3 deletions in PAI pathogenesis.

Main Methods:

  • Array comparative genomic hybridization was used to analyze patients with unexplained childhood-onset PAI.
  • Three-dimensional (3D) structure modeling and in vitro functional assays were employed to study ZNRF3 exon 2 deletions.

Main Results:

  • Single-exon deletions of ZNRF3 exon 2 were identified in three patients with neonatal-onset adrenal hypoplasia.
  • These deletions resulted in a truncated protein (ΔEx2-ZNRF3) that impairs RSPO1 binding and Wnt/β-catenin signaling activation.
  • Functional assays confirmed attenuated Wnt/β-catenin signaling in cells expressing ΔEx2-ZNRF3.

Conclusions:

  • Genetic evidence links ZNRF3 exon 2 deletions to congenital adrenal hypoplasia.
  • Constitutive inactivation of Wnt/β-catenin signaling by ΔEx2-ZNRF3 is a potential mechanism for PAI.
Keywords:
Wnt-β-catenin signalingadrenal hypoplasiazinc and ring finger 3

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