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Functional study of a novel c.630delG (p.Y211Tfs*85) mutation in NR5A1 gene in a Chinese boy with 46,XY disorders of sex development

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

This study aimed to present the clinical features and gene mutation characteristics of a child with 46,XY disorders of sex development (DSD) caused by a novel heterozygous mutation in the NR5A1 gene to determine the potential association between this heterozygous mutation and the pathogenesis of 46,XY DSD.

Methods

We present the case of a Chinese child with ambiguous genitalia at birth but a normal adrenal gland. Targeted next-generation sequencing, comprising 163 candidate genes involved in sexual differentiation and development, was performed, followed by the functional evaluation of the novel NR5A1 mutation.

Result

The patient had a novel heterozygous mutation in the NR5A1 gene, c.630delG (p.Y211Tfs*85). Results revealed that overexpression of p.Y211Tfs*85 impaired steroidogenic factor-1 (SF-1) protein synthesis. Immunofluorescence analysis revealed that both SF-1 wild-type and p.Y211Tfs*85 mutation proteins were localized in the cell nucleus. Furthermore, dual-luciferase reporter assay results revealed that the p.Y211Tfs*85 mutation could effectively downregulate the transcriptional activation of anti-Müllerian hormone and steroidogenic acute regulatory protein genes (P < 0.01). Additionally, the p.Y211Tfs*85 mutation changed three-dimensional conformation of SF-1, and three conformations could be constructed with the mutated amino acid sequences. Therefore, the novel frameshift mutation could result in decreased protein expression of SF-1.

Conclusion

We described a novel mutation in NR5A1 and showed that it might affect protein structure, thereby seriously compromising the role of SF-1 in regulating gonadal development. The novel p.Y211Tfs*85 mutation in the NR5A1 gene enriches the boy of information available regarding the mutation spectrum of this gene in the Chinese population.

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Funding

This work was supported by the Guangdong Science and Technology project (grant number 2012B031800077).

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Author notes

  1. Sinian Pan and Shili Guo contributed equally to this work.

Authors and Affiliations

  1. The Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China

    Sinian Pan, Shili Guo, Liting Liu, Xiaoyuan Yang & Hanmei Liang

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  1. Sinian Pan
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  2. Shili Guo
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  3. Liting Liu
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  4. Xiaoyuan Yang
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Contributions

• Sinian Pan and Shili Guo: Formal analysis, funding acquisition, investigation,; methodology, writing original draft

• Liting Liu: Supervision, validation

• Xiaoyuan Yang and Hanmei Liang: Review and editing

Corresponding author

Correspondence to Sinian Pan.

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Ethics statement

The Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University approved the collection of tissue samples for research.

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The authors declare that they have no conflict of interest.

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Highlights

We identified a patient with a novel heterozygous mutation in the NR5A1 gene, c.630delG (p.Y211Tfs*85).

The NR5A1 c.630delG p.Y211Tfs*85 mutation could effectively downregulate the transcriptional activation of the AMH and STAR.

This novel frameshift mutation resulted in a decreased protein expression of SF-1.

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Pan, S., Guo, S., Liu, L. et al. Functional study of a novel c.630delG (p.Y211Tfs*85) mutation in NR5A1 gene in a Chinese boy with 46,XY disorders of sex development. J Assist Reprod Genet 37, 477–486 (2020). https://doi.org/10.1007/s10815-019-01676-7

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  • DOI: https://doi.org/10.1007/s10815-019-01676-7

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