Rites of passage through puberty: A complex genetic ensemble

Jameson, J. Larry

doi:10.1073/pnas.0708636104

Cited by 7 publications

(5 citation statements)

References 16 publications

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“…Investigations of its genetic basis have helped elucidate some of the genes and mechanisms involved in the initiation of puberty. These insights have been critical in opening new avenues for basic research into the neuroendocrine control of mammalian reproduction (6, 7). Clinically, however, a definitive differential diagnosis between CDP and IHH remains virtually impossible before age 16, a feature that does not help to alleviate the child’s developmental delay, its social and psychological consequences, and the family’s anxiety.…”

Section: Gnrh Deficiency As a Paradigm Of Translational Medicinementioning

confidence: 99%

“…1). Genes harboring defects that cause GnRH deficiency have been demonstrated to play critical roles in the ontogeny (i.e., fate specification, proliferation, developmental migration, homeostasis, secretory function, and apoptosis) of GnRH neurons when studied in species that allow reductionist experimental approaches not possible in humans (6, 7, 10). …”

Section: Charting Reproductive Biology Through Human Geneticsmentioning

confidence: 99%

“…In addition to charting the regulation of GnRH neuron ontogeny and function, translational studies of IHH have challenged the monogenic view by demonstrating unexpected complexity in the genetic architecture of human GnRH deficiency (6, 7). With mutations in no fewer than 16 different genes described to date, the locus heterogeneity of IHH is impressive (Fig.…”

Section: Mending the Schism Between Monogenic And Common Diseasesmentioning

confidence: 99%

“…The first 20 years of genetic studies on isolated GnRH deficiency have yielded momentous insights into the biology of GnRH and the causes of its dysregulation (6, 7, 10). The next 20 years should herald the thorough genetic elucidation of this disease, the complete expansion of its phenotypic spectrum, and the translation of these advancements into diagnostic, prognostic, and therapeutic innovations.…”

Section: A Call For International Cooperationmentioning

confidence: 99%

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Deciphering Genetic Disease in the Genomic Era: The Model of GnRH Deficiency

et al. 2010

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Congenital gonadotropin-releasing hormone (GnRH) deficiency is a treatable albeit rare form of reproductive failure that has revealed physiological mechanisms controlling human reproduction, but despite substantial progress in discovering pathogenic single-gene defects, most of the genetic basis of GnRH deficiency remains uncharted. Although unbiased genetic investigations of affected families have identified mutations in novel genes as causes of this disease, their application has been severely limited because of the negative effect of GnRH deficiency on fertility; moreover, relatively few of the many candidate genes nominated because of biological plausibility from in vitro or animal model experiments were subsequently validated in patients. With the advent of exciting technological platforms for sequencing, homozygosity mapping, and detection of structural variation at the whole-genome level, human investigations are again assuming the leading role for gene discovery. Using human GnRH deficiency as a paradigm, we discuss the emerging model of patient-focused clinical genetic research and its complementarities with basic approaches in the near future.

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Section: Gnrh Deficiency As a Paradigm Of Translational Medicinementioning

confidence: 99%

Section: Charting Reproductive Biology Through Human Geneticsmentioning

confidence: 99%

Section: Mending the Schism Between Monogenic And Common Diseasesmentioning

confidence: 99%

Section: A Call For International Cooperationmentioning

confidence: 99%

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Deciphering Genetic Disease in the Genomic Era: The Model of GnRH Deficiency

et al. 2010

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“…Isolated GnRH deficiency can be sporadic or inherited as an autosomaldominant, autosomal-recessive, or X-linked trait (13). Genetic dissection of this disorder has led to the discovery of several new loci (>12) with critical roles for the developmental and neuroendocrine control of mammalian reproduction (12,14,15). Genes underlying isolated GnRH deficiency have been shown to be important for the specification and proliferation of GnRH neurons (16,17), their migration to the hypothalamus during embryonic development (18)(19)(20)(21)(22), the regulation of GnRH secretion (23)(24)(25), and the response of pituitary gonadotropes to Author contributions: G.P.S.…”

mentioning

confidence: 99%

Oligogenic basis of isolated gonadotropin-releasing hormone deficiency

Sykiotis

Plummer

Hughes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

318

260

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Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.rare variant | idiopathic hypogonadotropic hypogonadism | Kallmann syndrome | digenic | FGFR1

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