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Case Reports
. 2012 Aug;167(2):209-16.
doi: 10.1530/EJE-12-0127. Epub 2012 May 22.

A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia

Oded Breuer  1 , Maha Abdulhadi-Atwan, Sharon Zeligson, Hila Fridman, Paul Renbaum, Ephrat Levy-Lahad, David H Zangen
Affiliations
Case Reports

A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia

Oded Breuer et al. Eur J Endocrinol. 2012 Aug.

Abstract

Background: Kisspeptin 1 receptor (KISS1R) gene mutations are rare but have recently become an important etiology of normosmic isolated hypogonadotropic hypogonadism (IHH).

Objectives: To characterize the genetic defect, the phenotype, and response to therapy of three IHH siblings with a novel severe KISS1R mutation.

Patients and methods: Three siblings (16- and 22-year-old sisters and their 20-year-old brother) born to consanguineous parents with normal neonatal external genitalia presented with no pubertal development, normosmia, and a low response to GNRH stimulation. Homozygosity mapping, KISS1R gene sequencing, and RNA expression were performed.

Results: The females' basal low estradiol level (50 pmol/l) failed to rise in response to human chorionic gonadotropin (hCG). The brother's low testosterone (1.87 nmol/l) responded to combined hCG and human menopausal gonadotropin (hCG) and HMG therapies, but the testes remained small (1-2 ml). Secondary sexual characteristics were attained by exogenous sex steroid replacement. SNP array studies revealed shared homozygosity for a chromosome 19 region encompassing KISS1R. Sequencing revealed a novel homozygous KISS1R mutation at the nt-1 canonical acceptor splice site of intron 1 in affected siblings. The mother (menarche at 14 years) was heterozygous. cDNA sequencing showed that the G>A mutation results in skipping of exon 2 and a premature stop codon at residue 151.

Conclusions: The novel severe N-terminal KISS1R splice site (c.245-1G>A) mutation results in IHH. Heterozygous female carriers may manifest a subtle fertile phenotype. The subnormal gonadal response to hCG in patients may implicate a direct role of KISS1R in gonadal function. The normal neonatal virilization in a male homozygous to this severe mutation challenges the hypothesis that KISS1R is required for fetal development of male external genitalia.

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