Abstract
Kallmann syndrome (KS) is a developmental disease that associates hypogonadism and a deficiency of the sense of smell. The reproductive phenotype of KS results from the primary interruption of the olfactory, vomeronasal, and terminal nerve fibers in the frontonasal region, which in turn disrupts the embryonic migration of neuroendocrine gonadotropin-releasing hormone (GnRH) synthesizing cells from the nose to the brain. This is a highly heterogeneous genetic disease, and mutations in any of the nine genes identified so far have been found in approximately 30% of the KS patients. PROKR2 and PROK2, which encode the G protein-coupled prokineticin receptor-2 and its ligand prokineticin-2, respectively, are two of these genes. Homozygous knockout mice for the orthologous genes exhibit a phenotype reminiscent of the KS features, but biallelic mutations in PROKR2 or PROK2 (autosomal recessive mode of disease transmission) have been found only in a minority of the patients, whereas most patients carrying mutations in these genes are heterozygotes. The mutations, mainly missense mutations, have deleterious effects on PROKR2 signaling in transfected cells, ranging from defective cell surface-targeting of the receptor to defective coupling to G proteins or impaired receptor-ligand interaction, but the same mutations have also been found in apparently unaffected individuals, which suggests a digenic/oligogenic mode of inheritance of the disease in heterozygous patients. This non-Mendelian mode of inheritance has so far been confirmed only in a few patients. However, it may account for the unusually high proportion of KS sporadic cases compared to familial cases.
Highlights
Kallmann syndrome (KS) is a developmental disease that associates hypogonadotropic hypogonadism, due to gonadotropinreleasing hormone (GnRH) deficiency, and anosmia, related to the absence or hypoplasia of the olfactory bulbs (Kallmann, 1944; deMorsier, 1954; Naftolin et al, 1971)
Pathohistological studies of fetuses with olfactory bulb agenesis have shown that the reproductive phenotype of KS results from a pathological sequence in embryonic life, whereby premature interruption of the olfactory, vomeronasal, and terminal nerve fibers in the frontonasal region disrupts the migration of neuroendocrine GnRH cells, which normally migrate from the nose to the brain along these nerve fibers (Schwanzel-Fukuda and Pfaff, 1989; Teixeira et al, 2010)
Plasma cortisol levels were measured during 24 h in five patients mutated in PROK2 or PROKR2, including one patient with biallelic PROKR2 mutations, and normal circadian variation was observed in all cases (Sarfati et al, 2010), which argues against a major contribution of PROK2/PROKR2 signaling to physiological circadian variation of plasma cortisol levels in humans
Summary
Kallmann syndrome (KS) is a developmental disease that associates hypogonadotropic hypogonadism, due to gonadotropinreleasing hormone (GnRH) deficiency, and anosmia, related to the absence or hypoplasia of the olfactory bulbs (Kallmann, 1944; deMorsier, 1954; Naftolin et al, 1971). The prevalence is thought to be five times lower, but it is probably underestimated because some affected females only have mild hypogonadism, and because primary amenorrhea in females often remains unexplored (Jones and Kemmann, 1976). Kallmann syndrome is genetically heterogeneous and involves various modes of transmission, X-chromosome linked, autosomal recessive, autosomal dominant with incomplete penetrance, and digenic/oligogenic inheritance (Dodé and Hardelin, 2009; Sykiotis et al, 2010). Because the common infertility in affected individuals and, most importantly, the incomplete penetrance of the disease impede genetic linkage analysis, researchers have used various strategies to identify genes involved in KS, including mutation screening in genes that are disrupted by deletion or translocation breakpoints in chromosomal rearrangements associated with the disease phenotype, and candidate gene approaches. Mutations in KAL1 and FGFR1/FGF8 account for roughly 8 and 10% of www.frontiersin.org
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