Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

Tata, Brooke; Huijbregts, Lukas; Jacquier, Sandrine; Csaba, Zsolt; Génin, Emmanuelle; Meyer, Vincent; Leka, Sofia; Dupont, Joëlle; Charles, Perrine; Chevenne, Didier; Carel, Jean‐Claude; Léger, Juliane; Roux, Nicolas de

doi:10.1371/journal.pbio.1001952

Cited by 71 publications

(81 citation statements)

References 57 publications

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“…Homozygosity mapping (73), candidate gene screening (74), and whole-exome sequencing prompted the discovery of kisspeptin (KISS1) mutations in a consanguineous nIHH family (73), whereas mutations in the fasciculation and elongation protein zeta family zinc finger 1 (FEZF1) were newly identified in consanguineous KS families of Kurdish origin (75). Most recently, linkage analysis revealed a homozygous deletion in Drosophila melanogaster X-gene like-2 (DMXL2) gene carried by 3 brothers of a Senegalese consanguineous pedigree affected with a syndromic form of IGD that includes hypothyroidism, diabetes mellitus, and various neurological phenotypes (76). These examples suggest that analysis of other endogamous pedigrees will allow researchers to uncover novel recessive genes, giving additional insights into IGD disease pathology.…”

Section: Endogamous Pedigrees Lead To the Discovery Of Recessive Imentioning

confidence: 99%

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015

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The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3) substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015)

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Section: Endogamous Pedigrees Lead To the Discovery Of Recessive Imentioning

confidence: 99%

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015

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“…In 2014, haploinsufficiency of DMXL2, which encodes synaptic protein DmX-like protein 2, was shown to cause a complex new syndrome associating CHH with polyendocrine deficiencies and polyneuropathies. 57 Peripheral signals that convey information about metabolic status indirectly modulate GnRH neuro secretion. This modulation is well illustrated by the reproductive phenotype of absent pubertal development and hypogonadotropic hypogonadism in patients with inactivating mutations in the genes encoding leptin (LEP) or its receptor (LEPR).…”

Section: Virilization (Male)mentioning

confidence: 99%

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

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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“…Homozygosity mapping (73), candidate gene screening (74), and whole-exome sequencing prompted the discovery of kisspeptin (KISS1) mutations in a consanguineous nIHH family (73), whereas mutations in the fasciculation and elongation protein zeta family zinc finger 1 (FEZF1) were newly identified in consanguineous KS families of Kurdish origin (75). Most recently, linkage analysis revealed a homozygous deletion in Drosophila melanogaster X-gene like-2 (DMXL2) gene carried by 3 brothers of a Senegalese consanguineous pedigree affected with a syndromic form of IGD that includes hypothyroidism, diabetes mellitus, and various neurologic phenotypes (76). These examples suggest that analysis of other endogamous pedigrees will allow researchers to uncover novel recessive genes, giving additional insights into IGD disease pathology.…”

Section: Endogamous Pedigrees Lead To the Discovery Of Recessive Imentioning

confidence: 99%

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015

View full text Add to dashboard Cite

The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamicpituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.

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Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

Abstract: Rabconnectin-3α and the control of puberty Human genetics shows that low levels of rabconnectin-3α cause a loss of the neurons that produce gonadotropin-releasing hormone, revealing a new mechanism for incomplete puberty and infertility.

Cited by 71 publications

References 57 publications

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

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

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

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