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
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.
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.
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.
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.
KeywordsNR5A1 SF-1 AMH STAR Disorders of sex development
• 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
This work was supported by the Guangdong Science and Technology project (grant number 2012B031800077).
Compliance with ethical standards
The Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University approved the collection of tissue samples for research.
Conflict of interest
The authors declare that they have no conflict of interest.
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