ESPEYB21 8. Adrenals New Genes (1 abstracts)
8.16. Single-exon deletions of ZNRF3 exon 2 cause congenital adrenal hypoplasia
Amano N , Narumi S , Aizu K , Miyazawa M , Okamura K , Ohashi H , Katsumata N , Ishii T & Hasegawa T
J Clin Endocrinol Metab. 2024; 109(3): 641-648. https://pubmed.ncbi.nlm.nih.gov/37878959/
Brief Summary: This study identifies a novel cause for congenital adrenal hypoplasia and provides evidence that Wnt/β-catenin signaling plays an important role in the development of human adrenal cortex.
Comment: Primary adrenal insufficiency (PAI) is a life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient glucocorticoids and/or mineralocorticoids. The major cause of childhood-onset PAI is congenital adrenal hyperplasia, such as 21-hydroxylase deficiency (1), however, a small subset of patients lack a known cause for their disorder.
These authors enrolled patients with PAI (n=9) of genetically unknown cause. They used array comparative genomic hybridization to identify a heterozygous deletion of exon 2 in the zinc and ring finger 3 ( ZNRF3 ) gene. Further studies showed that this deletion results in the expression of a 42-amino acid shorter protein. Loss of this exon impaired interaction between ZNRF3 and RSPO1 on 3D modelling, indicating a potential defect in the RSPO1-dependent activation of the Wnt/β-catenin pathway. In a cell-based functional assay, RSPO1-dependent activation of the Wnt/β-catenin pathway was indeed impaired, indicating the importance of ZNRF3 in the development of the adrenal cortex. These findings extend the list of genetic causes of PAI.
Reference: 1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000; 21(3): 245-291.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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