Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome

Abstract

We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.

Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy

“…PROKR1-I379V and PROKR2-V331M are located in the intracellular C-terminal domains of GPCRs, and the change of amino acid may alter the process of G-protein (Gq, Gs, and Gi) coupling and intracellular calcium influx (Masuda et al 2002, Abreu et al 2008, Levit et al 2011, McCoy et al 2012. Intracellular Ca 2C is an Prokineticin receptor genes and recurrent miscarriage important second messenger, and the downstream effects of calcium mobilization are likely to be numerous and may include activation of various secretory and signaling pathways (Petit & Bélisle 1995, Karl et al 1997, Tinel et al 2000.…”

“…Several PROKR2 mutations are reported to be related to Kallmann syndrome (KS) and idiopathic hypogonadotrophic hypogonadism (IHH) (Dodé et al 2006, Pitteloud et al 2007, Abreu et al 2008, Cole et al 2008, Leroy et al 2008, Canto et al 2009, Sarfati et al 2010. Most of these mutations have various functional effects, including altering calcium mobilization, MAPK activation, or receptor trafficking (Abreu et al 2010, Peng et al 2011.…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”

Estudo do gene do receptor de GnRH (GNRHR) no hipogonadismo hipogonadotrófico isolado normósmico e atraso constitucional do crescimento e desenvolvimento

“…Estes genes codificam uma rede complexa de fatores de transcrição, proteínas de matriz, neurotransmissores, enzimas e receptores hormonais que apresentam ações fundamentais para a aquisição e manutenção de uma função reprodutiva normal (19,20) . (10,(21)(22)(23) . Os genes associados à secreção e ação de GnRH, tais como GnRH, GNRHR, KISS1, KISSR, TAC3, TAC3R, estão implicados exclusivamente na patogênese de HHI normósmico (24) .…”