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Single-exon deletions of ZNRF3 exon 2 cause congenital adrenal hypoplasia.
Journal of Clinical Endocrinology and Metabolism 2023 October 26
CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient steroid hormones. E3 ubiquitin protein ligase zinc and ring finger 3 (ZNRF3) is a negative regulator of Wnt/β-catenin signaling. R-spondin 1 (RSPO1) enhances Wnt/β-catenin signaling via binding and removal of ZNRF3 from the cell surface.
OBJECTIVE: This work aimed to explore a novel genetic form of PAI.
METHODS: We analyzed nine childhood-onset patients with PAI of biochemically and genetically unknown etiology using array comparative genomic hybridization. To examine the functionality of the identified single-exon deletions of ZNRF3 exon 2, we performed three-dimensional structure modeling and in vitro functional studies.
RESULTS: We identified various-sized single-exon deletions encompassing of ZNRF3 exon 2 in three patients, who showed neonatal-onset adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiencies. RT-PCR analysis showed that the three distinct single exon deletions were commonly transcribed into a 126-nucleotide deleted mRNA and translated into 42-amino acid deleted protein (ΔEx2-ZNRF3). Based on three-dimensional structure modeling, we predicted that interaction between ZNRF3 and RSPO1 would be disturbed in ΔEx2-ZNRF3, suggesting loss of RSPO1-dependent activation of Wnt/β-catenin signaling. Cell-based functional assays with the TCF-LEF reporter showed that RSPO1-dependent activation of Wnt/β-catenin signaling was attenuated in cells expressing ΔEx2-ZNRF3 as compared with those expressing wild-type ZNRF3.
CONCLUSION: We provided genetic evidence linking deletions encompassing ZNRF3 exon 2 and congenital adrenal hypoplasia, which might be related to constitutive inactivation of Wnt/β-catenin signaling by ΔEx2-ZNRF3.
OBJECTIVE: This work aimed to explore a novel genetic form of PAI.
METHODS: We analyzed nine childhood-onset patients with PAI of biochemically and genetically unknown etiology using array comparative genomic hybridization. To examine the functionality of the identified single-exon deletions of ZNRF3 exon 2, we performed three-dimensional structure modeling and in vitro functional studies.
RESULTS: We identified various-sized single-exon deletions encompassing of ZNRF3 exon 2 in three patients, who showed neonatal-onset adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiencies. RT-PCR analysis showed that the three distinct single exon deletions were commonly transcribed into a 126-nucleotide deleted mRNA and translated into 42-amino acid deleted protein (ΔEx2-ZNRF3). Based on three-dimensional structure modeling, we predicted that interaction between ZNRF3 and RSPO1 would be disturbed in ΔEx2-ZNRF3, suggesting loss of RSPO1-dependent activation of Wnt/β-catenin signaling. Cell-based functional assays with the TCF-LEF reporter showed that RSPO1-dependent activation of Wnt/β-catenin signaling was attenuated in cells expressing ΔEx2-ZNRF3 as compared with those expressing wild-type ZNRF3.
CONCLUSION: We provided genetic evidence linking deletions encompassing ZNRF3 exon 2 and congenital adrenal hypoplasia, which might be related to constitutive inactivation of Wnt/β-catenin signaling by ΔEx2-ZNRF3.
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