Background: Loss of function mutations in KISS1R, which encodes kisspeptin receptor have been reported in very few patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).
Objective and hypotheses: To describe the phenotype of the nIHH female patient with a novel homozygous KISS1R mutation and to characterize functionally this mutation. The patient was a 28 year-old Senegalese woman with primary amenorrhea. She was the second child born to consanguineous parents. Hormone assays revealed low levels of estradiol and inappropriate normal levels of gonadotropins. Brain MRI showed normal pituitary and olfactory bulbs. Pelvic ultrasonography showed a small uterus and right small ovary with follicles. Her karyotype was 46,XX.
Method: Exon and exon-intron boundaries of nIHH candidate genes were sequenced. Functional analysis of the mutated receptor was performed by intracellular inositol phosphate measurement, western blot and immunofluorescence staining in heterologous cells.
Results: A novel homozygous mutation c.953T>C was identified in the proband, leading to the amino acid substitution of leucine 318 by proline (p.L318P). Functional analysis showed impaired inositol phosphate generation under kisspeptin stimulation. The mutated receptor was not detected at the cell surface in transfected HEK 293 cells. Western blot analysis showed the absence of mature glycosylated receptor but the presence of an immature form.
Conclusion: The nIHH observed in this patient is due to a novel loss-of-function mutation in KISS1R. The L318P substitution impedes the intracellular trafficking of KiSSR. This patient is a novel candidate to a treatment by a chemical chaperone to rescue expression of the mutated receptor at the cell surface.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology