Abstract
KISS1R (GPR54) mutations have been reported in several patients with congenital normosmic idiopathic hypogonadotropic hypogonadism (nIHH). We aim to describe in detail nIHH patients with KISS1R (GPR54) mutations belonging to one related extended family and to review the literature. A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in three affected kindred (2 males and 1 female) from a consanguineous Saudi Arabian family. This residue is localized within the first exoloop of the receptor, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs its function. In the affected female, a combined gonadotropin administration restored regular period and ovulation and she conceived with a healthy baby boy after 4 years of marriage. We showed that a loss-of-function mutation (p.Tyr305C) in the KISS1R gene can cause (L102P) KISS1 receptor dysfunction and familial nIHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of periods and later on pregnancy by an exogenous gonadotropin administration further support, in humans, that the KISS1R mutation has no other harmful effects on the patients apart from the gonadotropin secretion impairment.
Highlights
Hereditary isolated hypogonadotropic hypogonadism (IHH) is an uncommon disorder in pediatric and adult population; genetic causes of IHH are increasingly recognized due to the increasing number of genetic testing.Genetic IHH is classified into two types, depending on the presence or absence of smell defect: Kallmann syndrome when associated with anosmia and normosmic IHH when normal smell is preserved.Neuroendocrine control of the reproductive axis in humans rests with a group of neurons called GnRH neurons, approximately 1500 in number and dispersed in the hypothalamus
We described a loss-of-function mutation in the homozygous state, previously described by Yardena et al (p.Tyr305C) in the KISS1R (GPR54) gene leading to p.Leu102Pro in the KISS1 receptor in a highly consanguineous Saudi Arabian family suffering from congenital normosmic idiopathic hypogonadotropic hypogonadism (nIHH) [5]
Functional analyses in a previous study by Yardena et al revealed that the L102P variant led to an almost complete loss-of-function mutation, resulting in a severe phenotype corresponding to lack of pubertal development with cryptorchidism [5]
Summary
Received 14 May 2019; Revised 27 August 2019; Accepted 10 September 2019; Published 16 October 2019. KISS1R (GPR54) mutations have been reported in several patients with congenital normosmic idiopathic hypogonadotropic hypogonadism (nIHH). We aim to describe in detail nIHH patients with KISS1R (GPR54) mutations belonging to one related extended family and to review the literature. Is residue is localized within the first exoloop of the receptor, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs its function. We showed that a loss-offunction mutation (p.Tyr305C) in the KISS1R gene can cause (L102P) KISS1 receptor dysfunction and familial nIHH, revealing the crucial role of this amino acid in KISS1R function. E observed restoration of periods and later on pregnancy by an exogenous gonadotropin administration further support, in humans, that the KISS1R mutation has no other harmful effects on the patients apart from the gonadotropin secretion impairment We showed that a loss-offunction mutation (p.Tyr305C) in the KISS1R gene can cause (L102P) KISS1 receptor dysfunction and familial nIHH, revealing the crucial role of this amino acid in KISS1R function. e observed restoration of periods and later on pregnancy by an exogenous gonadotropin administration further support, in humans, that the KISS1R mutation has no other harmful effects on the patients apart from the gonadotropin secretion impairment
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