New understandings of the genetic basis of isolated idiopathic central hypogonadism

Abstract

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network. Asian Journal of Andrology (2012) 14, 49-56; doi:10.1038/aja.2011.68; published online 5 December 201

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform

“…Our study of 50 patients with IHH identified six novel heterozygous FGFR1 mutations, including a mutation in the alternatively spliced exon 8A of this gene. The frequency of FGFR1 mutations in KS and in normosmic IHH probands was 14% (3 in 21) and 10% (3 in 29), respectively, which is consistent with results presented in other studies (6,13,14,(23)(24)(25)(26)(27).…”

The role of the genetic factors in pathogenesis of hypogonadotropic hypogonadism

“…Гены FGF8 и FGFR1 кодируют соответственно фактор роста фибробластов (FGF8) и его рецептор и непосредственно участвуют в онтогенезе нейронов ГнРГ. Снижение экспрессии FGF8 ингибирует диф-ференцировку клеток-предшественников в нейроны ГнРГ [12,13]. Ген FGFR1 участвует в спецификации нейронов в обонятельной плакоде [14].…”

“…Группа генов -PROK2/PROKR2, KAL1, CHD7, FGFR1 контролирует миграцию нейронов ГнРГ1 от места эмбрионального происхождения в гипотала-мус. Продукт гена FGFR1 влияет на развитие обоня-тельной луковицы и на миграционную активность нейронов ГнРГ1 [12]. Гены PROK1/PROKR1 и PROK2/PROKR2 кодируют компоненты прокинети-цитиновой системы, состоящей из двух почти иден-тичных (на 85%) рецепторов (PROKR1 и PROKR2) и двух их лигандов (PROK1 и PROK2).…”

“…Комплексы рецептор-лиганд KISS1/KISS1R, TAC3/TACR3, LEP/LEPR и ген PCSK1 кодируют белки, способствующие активации нейронов ГнРГ1, и, тем самым, регулируют секрецию ГнРГ [12,24]. Ген KISS1 кодирует белок кисспептин.…”

“…Пара рецептор-лиганд KISS1/KISS1R оказывает стиму-лирующий эффект на высвобождение ГнРГ и по-следующий синтез гонадотропинов. KISS1-секретирующие нейроны чувствительны к эстроге-ну и вовлечены в механизм отрицательной и поло-жительной обратной связи [12]. У пациентов с нИГГ из-за мутаций в гене KISS1R серьезно снижается амплитуда импульсов ЛГ, но сохраняется нормаль-ная их частота [15].…”