Enhanced at Puberty-1 (Eap1) Expression Critically Regulates the Onset of Puberty Independent of Hypothalamic Kiss1 Expression

Li, Chenxi; Пин, Ли

doi:10.1159/000481872

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…Although little is known about IRF2BPL and Pits, most studies implicate their localization and function in the nucleus. 30,58,60,76,77 However, the RING domain of IRF2BPL has recently been shown to act as an E3-ligase that ubiquitinates b-catenin and suppresses Wnt signaling in gastric cancer. 32 It is currently unclear whether this pathway might be altered in IRF2BPL-associated disease.…”

Section: Neuronal Knock-down Of Pits Causes Progressivementioning

confidence: 99%

IRF2BPL Is Associated with Neurological Phenotypes

Marcogliese¹,

Shashi²,

Spillmann³

et al. 2018

The American Journal of Human Genetics

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Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

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Section: Neuronal Knock-down Of Pits Causes Progressivementioning

confidence: 99%

IRF2BPL Is Associated with Neurological Phenotypes

Marcogliese¹,

Shashi²,

Spillmann³

et al. 2018

The American Journal of Human Genetics

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show abstract

“…Although little is known about IRF2BPL/Pits, most studies implicate its expression and function in the nucleus. 30,57,59,74,75 . However, the RING domain of IRF2BPL has recently been shown to act as an E3-ligase ubiquitinating β-catenin and supressing Wnt signalling in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function in IRF2BPL is associated with neurological phenotypes

Marcogliese¹,

Shashi

Spillmann

et al. 2018

Preprint

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“…EAP1 binding to the GnRH1 promoter increases in monkey hypothalamus at the onset of puberty (Mancini et al 2019). Furthermore, knockdown of Eap1 with siRNAs causes delayed puberty and disrupted estrous cyclicity in rodents (Heger et al 2007, Xu & Li 2016, Li & Li 2017. Eap1 has dual transcriptional activity: it trans-activates the…”

Section: R42 S R Howardmentioning

confidence: 99%

Genetic regulation in pubertal delay

Howard

2019

Journal of Molecular Endocrinology

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Delayed puberty represents the clinical presentation of a final common pathway for many different pathological mechanisms. In the majority of patients presenting with significantly delayed puberty, there is a clear family history of delayed or disturbed puberty, and pubertal timing is known to be a trait with strong heritability. Thus, genetic factors clearly play a key role in determining the timing of puberty, and mutations in certain genes are recognised as responsible for delayed or absent puberty in a minority of patients. Through the identification of causal genetic defects such as these we have been able to learn a great deal about the pathogenesis of disrupted puberty and its genetic regulation. Firstly, deficiency in key genes that govern the development of the gonadotropin-releasing hormone system during fetal development may result in a spectrum of conditions ranging from isolated delayed puberty to absent puberty with anosmia. Secondly, a balance of inhibitory and excitatory signals, acting upstream of GnRH secretion, are vital for the correct timing of puberty. These act to repress the hypothalamic–pituitary–gonadal axis during mid-childhood and allow it to reactivate at puberty, and alterations in this equilibrium can cause delayed (or precocious) puberty. Thirdly, disturbances of energy metabolism inputs to the kisspeptin–GnRH system may also lead to late onset of puberty associated with changes in body mass.

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Enhanced at Puberty-1 (Eap1) Expression Critically Regulates the Onset of Puberty Independent of Hypothalamic Kiss1 Expression

Cited by 17 publications

References 29 publications

IRF2BPL Is Associated with Neurological Phenotypes

IRF2BPL Is Associated with Neurological Phenotypes

Loss-of-function in IRF2BPL is associated with neurological phenotypes

Genetic regulation in pubertal delay

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