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

BACKGROUND

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease attributed to the disorder of hypothalamic-pituitary-gonadal axis. Mutations in the gene are one of the most common genetic causes of IHH. Herein, we aimed to investigate 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. 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 RSV, we performed conservative analysis, crystal structure prediction, expression analysis as well as the assessment of ERK1/2 activation and IP3/Ca response.

RESULTS

The same heterozygous RSV (p.R240Q) in 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 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 mutation spectrum in IHH patients, and reveals that the 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.