A partial loss-of-function variant in GNRNR gene in a Chinese cohort with idiopathic hypogonadotropic hypogonadism

Yinwei Chen; Taotao Sun; Yonghua Niu; Daoqi Wang; Kang Liu; Tao Wang; Shaogang Wang; Hao Xu; Jihong Liu

doi:10.21037/tau-20-1390

A partial loss-of-function variant in GNRNR gene in a Chinese cohort with idiopathic hypogonadotropic hypogonadism

Transl Androl Urol. 2021 Apr;10(4):1676-1687. doi: 10.21037/tau-20-1390.

Authors

Yinwei Chen^{1

2}, Taotao Sun^{1

2}, Yonghua Niu³, Daoqi Wang^{1

2}, Kang Liu^{1

2}, Tao Wang^{1

2}, Shaogang Wang^{1

2}, Hao Xu^{1

2}, Jihong Liu^{1

2}

Affiliations

¹ Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Background: Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease attributed to the disorder of hypothalamic-pituitary-gonadal axis. Mutations in the GNRHR gene are one of the most common genetic causes of IHH. Herein, we aimed to investigate GNRHR variants in a Chinese cohort with IHH, and to characterize them at the molecular level.

Methods: A total of 153 IHH patients were recruited, and variants were detected using a tailored next-generation sequencing panel. GNRHR rare sequencing variant (RSV) was verified using Sanger sequencing. Phenotypic features and therapeutic outcomes of patients were followed up. In order to examine the pathogenicity of the GNRHR RSV, we performed conservative analysis, crystal structure prediction, expression analysis as well as the assessment of ERK1/2 activation and IP3/Ca²⁺ response.

Results: The same heterozygous RSV (p.R240Q) in GNRHR was identified in four sporadic IHH patients. These patients exhibited different severity of testicular development and hormone profile. hCG treatment was effective in improving gonadal development, serum testosterone, and semen quality. The GNRHR RSV has no effect on the expression of mRNA and protein, whereas damaged ERK1/2 activation and inositol triphosphate/calcium signaling.

Conclusions: The study expands GNRHR mutation spectrum in IHH patients, and reveals that the GNRHR RSV is a partial loss-of-function mutation. Although this heterozygous RSV may not have a significant influence on the pathogenesis of IHH, but its homozygous/ compound status should be paid attention in this research field.

Keywords: GNRHR; Idiopathic hypogonadotropic hypogonadism (IHH); heterozygote; phenotype; rare sequencing variant.