TY - JOUR
T1 - A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia
AU - Breuer, Oded
AU - Abdulhadi-Atwan, Maha
AU - Zeligson, Sharon
AU - Fridman, Hila
AU - Renbaum, Paul
AU - Levy-Lahad, Ephrat
AU - Zangen, David H.
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864371825&partnerID=8YFLogxK
U2 - 10.1530/EJE-12-0127
DO - 10.1530/EJE-12-0127
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C2 - 22619348
AN - SCOPUS:84864371825
SN - 0804-4643
VL - 167
SP - 209
EP - 216
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
IS - 2
ER -