Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G proteincoupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.
CYP24A1 biallelic mutations are frequently found in patients presenting with hypercalcemia, low PTH, and renal disease. We confirm the accuracy and effectiveness of a novel blood test estimating the ratio between relevant vitamin D metabolites as a useful screening tool for CYP24A1 mutations. Haploinsufficiency is not associated with CYP24A1 deficiency.
Kisspeptin, the product derived from KiSS-1, and its cognate receptor, GPR54, both exert a role in the neuroendocrine control of reproduction by regulating gonadotrophin-releasing hormone (GnRH) secretion. In the present study, we demonstrate, using dual immunofluorescence with specific antibodies, that the KiSS-1 and GPR54 genes are both expressed in rat gonadotrophs. All luteinising hormone beta-immunoreactive (LH beta-ir) cells were stained by the KiSS-1 antibody but some kisspeptin-ir cells were not LH beta positive; thus, we cannot exclude the possibility that kisspeptins are expressed in other pituitary cells. All GPR54-ir are co-localised with LH beta cells, but only a subset of LH beta cells are stained with the GPR54 antibody. Using the real-time reverse transcription-polymerase chain reaction (RT-PCR), we found that the expression of KiSS-1 and GPR54 is differentially regulated by steroids. In the female, KiSS-1 mRNA levels dramatically decreased following ovariectomy (OVX), and this decrease was prevented by administration of 17beta-oestradiol (E(2)), but not by administration of GnRH antagonist or agonist. Administration of E(2) in OVX rats receiving either GnRH antagonist or agonist clearly shows that E(2) acts directly on the pituitary to positively control KiSS-1 expression. In OVX rats, administration of the selective oestrogen receptor (ER)alpha ligand propylpyrazoletriol, but not the selective ER beta ligand diarylpropionitrile, mimics this effect. By contrast, our study shows that GPR54 expression is positively regulated by GnRH and negatively controlled by chronic exposure to E(2). In summary, our data document for the first time that, in the female rat pituitary, KiSS-1 expression is up-regulated by oestradiol, similarly to that seen in the anteroventral periventricular nucleus of the hypothalamus. Conversely, GPR54 is up-regulated by GnRH, which exclusively targets gonadotrophs.
This new deletion suggests that NESP55 is an additional imprinting control region that directs A/B methylation in humans. We bring arguments in support of the theory of reciprocal inhibition between the expression of NESP and AS. However, determining whether loss of methylation at the A/B differentially methylated region is a consequence of the loss of NESP expression or of the expression of AS requires additional investigations.
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