Rites of passage through puberty: A complex genetic ensemble
Worldwide, puberty is recognized by various cultures and celebrated as a rite of passage into adulthood. The methodical drumbeat of these religious and social ceremonies foreshadows the rhythm of reproduction that, in many ways, marks the final stage of development. Despite its social and physiological significance, including perpetuation of the species, the pathways that regulate the onset of puberty have evaded traditional physiological inquiries. No clear hormonal or metabolic trigger has been identified as a switch that activates the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator (1). Instead, geneticabnormalities that preclude puberty have provided the major insights into the pathways that are critical for the development and maturation of the reproductive axis (2, 3). Perhaps the best candidate for regulating the onset of puberty is kisspeptin, the ligand for the receptor encoded by GPR54, a gene identified as a cause of recessive hypogonadotropic hypogonadism (4, 5). The report by Pitteloud et al. (6) in this issue of PNAS identifies loss-of-function mutations in the prokineticin 2 (PROK2) gene, which encodes a secreted peptide that regulates the development and migration of the olfactory tract and GnRH neuron progenitors. The PROK2 mutations caused hypogonadotropic hypogonadism in both males and females. Using Prok2 −/− knockout mice, the GnRH neuron progenitors were shown to cross the cribriform plate but fail to migrate into and populate the hypothalamus. Interestingly, olfactory tract development in humans with PROK2 mutations was variable, resulting in both nonanosmic and anosmic forms of hypogonadotropic hypogonadism. This report highlights the role of genetics as a means to unravel complex developmental processes and helps explain why anosmia is a frequent, but variable, feature of inherited forms of hypogonadotropic hypogonadism.
Delayed puberty is a common clinical presentation and is often accompanied by delayed growth (7). The challenge for the practitioner is to distinguish those individuals with constitutional delay of growth and puberty (CDGP) from those with more serious conditions such as panhypopituitarism, growth hormone deficiency, or hypogonadotropic hypogonadism. When pubertal delay extends beyond 2–2.5 standard deviations of the mean age of puberty (approximately age 13 years in girls and 14 years in boys), it is termed idiopathic hypogonadotropic hypogonadism (IHH). Pubertal delay is more common in boys than in girls, and IHH is approximately five times more frequent in males. These observations suggest an important role for genes on the X chromosome or perhaps fundamental differences in the sensitivity of the neuronal circuitry to disruption by genetic, hormonal, or environmental effects in males. The genetic basis of X-linked Kallmann syndrome was identified in 1991 based on a contiguous gene syndrome that included the locus encoding anosmin (KAL1) (8, 9). Initially, it was thought that mutations in the X-linked KAL1 gene might explain why the disorder is more common in boys.
Moreover, the gene product affects migration of the precursor cells for the GnRH-producing neurons and the olfactory tracts, providing an explanation for the association of IHH and anosmia (10). Subsequent studies, however, identified KAL1 mutations in a minority of patients with familial or sporadic forms of IHH (2, 3). Moreover, pedigrees with clear-cut autosomal dominant and recessive patterns of transmission suggested the involvement of other genes (11). The ensuing years have yielded a surprising array of genetic causes of gonadotropin deficiency, affecting multiple steps in the pathways that culminate in GnRH and gonadotropin synthesis and secretion. As depicted in Fig. 1, genetic defects have been found in (i) GnRH neuron migration and function (KAL1, FGFR1, NELF, PROK2, and PROKR2), (ii) factors that regulate GnRH synthesis and release (GPR54, SF1, DAX1, LEP, and LEPR), (iii) GnRH response (GNRHR), and (iv) gonadotropin biosynthesis (LHB, FSHB, SF1, and DAX1).
Genetic causes of hypogonadotropic hypogonadism. The hypothalamic–pituitary–gonadal (HPG) axis is depicted in Right. Hypothalamic gonadotropin-releasing hormone (GnRH) pulses stimulate pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulses that act on the gonads to stimulate gametogenesis and sex steroid, which feed back to regulate the hypothalamus and pituitary. Genes associated with hypogonadotropic hypogonadism are listed in Left below the steps they regulate. KAL1, Kallmann syndrome gene 1 (encodes anosmin 1); FGFR1, fibroblast growth factor receptor 1; NELF, nasal embryonic luteinizing hormone releasing hormone factor; PROK2, prokineticin 2; PROKR2, prokineticin receptor 2; GPR54, G protein receptor 54; LEP, leptin; LEPR, leptin receptor; SF1, steroidogenic factor 1 (also FTZF1 or NR5A1); DAX1, dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on X chromosome 1 (also, NROB1); GNRHR, GnRH receptor; LHB, LH-β; FSHB, FSH-β.
Access to a large group of patients with an uncommon disorder is invaluable when multiple genes cause similar phenotypes. In the study by Pitteloud et al. (6), subjects with known genetic causes of IHH were excluded from a group of 100 probands with normosmic or anosmic IHH. From this group, they identified a single family with a homozygous deletion causing a frameshift mutation in PROK2. Heterozygous carriers of this PROK2 mutation had normal smell and fertility. In another recent study, Dode et al. (12) identified four potential heterozygous PROK2 mutations from a cohort of 192 patients. Of note, neither KAL1 nor PROKR2 mutations were found in the subjects with heterozygous PROK2 mutations. Thus, these individuals may harbor undetected mutations in PROK2 or other genes in the pathway governing development of the GnRH neurons. They also identified several potential mutations in PROKR2 (12), a gene encoding the receptor for prokineticin 2, underscoring the role of this pathway for olfactory and GnRH neuron development. Taken together, these studies suggest that PROK2 or PROKR2 mutations account for a relatively small fraction, perhaps 5%, of IHH. Combined with mutations in other known genes (KAL1, FGFR1, NELF, and GPR54) associated with isolated GnRH deficiency, the current candidates account for ≈30% of cases, indicating that other genes remain to be discovered.
The KAL1 gene product, anosmin 1, has been proposed to enhance FGFR1 signaling (13). Prokineticin 2 and its receptor may somehow converge with this pathway to orchestrate the migration and development of
GnRH neurons (12). Of note, the prokineticin 2 receptor is not colocalized with the GnRH
Anosmia is a frequent, but variable, feature of inherited forms of hypogonadotropic hypogonadism.
(6), suggesting that the prokineticin pathway acts on these neurons indirectly, perhaps by establishing a migratory pathway.
Prokineticin 2 is also expressed in the suprachiasmatic nucleus, where it oscillates in a circadian manner (14). Mice deficient in Prok2 exhibit reduced total sleep time and impaired compensatory sleep after sleep deprivation. It remains to be seen whether humans
with PROK2 mutations have sleep disturbances and the metabolic abnormalities that sometimes accompany altered sleep cycles.
Why has it been relatively difficult to identify the genetic causes of IHH? One obvious reason is that the reproductive abnormalities limit transmission and pedigree size, thereby reducing the power of traditional linkage analyses. Genetic heterogeneity, manifest by different modes of transmission (X-linked, autosomal dominant, and autosomal recessive), as well as the growing list of candidate genes, is another hurdle. Variable penetrance of clinical features (e.g., anosmia), even within a family, remains incompletely understood and may reflect the involvement of multiple genes, epistasis, or redundant pathways.
The finding that multiple genetic alterations can result in a similar clinical phenotype foreshadows the possibility of digenic or polygenic causes of IHH. A common observation in mouse models is that the phenotype of a particular mutation varies on different genetic backgrounds, illustrating the effects of modifier genes (15). These effects can be relatively weak or profound depending on the genetic pathway and the functional importance of the modifier gene. Patients with IHH are now being identified with combinatorial mutations in genes that act in the same pathway or at different steps in the reproductive axis. For example, recent studies have documented digenic inheritance of mutations of IHH genes (FGFR1 in combination with GNRHR; FGFR1 in combination with NELF; or FGFR1 in combination with PROKR2) (12, 16). These observations suggest the possibility of dose effects of various genes in the pathway of GnRH production, release, or action. Thus, one can envision a wide array of gene dosage effects acting in combination to cause IHH or to modify the phenotype of IHH. These genes, and those that remain to be discovered, are also likely candidates for familial contributions to the onset of puberty (7). Soon, we may know enough about the genetic basis of IHH to drop the description “idiopathic” from the name.
Footnotes
- *E-mail: ljameson{at}northwestern.edu
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Author contributions: J.L.J. wrote the paper.
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The author declares no conflict of interest.
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See companion article on page 17447.
- © 2007 by The National Academy of Sciences of the USA
