ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure

Delcour, Clémence; Amazit, Larbi; Patiño, Liliana Catherine; Magnin, F; Fagart, Jérôme; Delemer, Brigitte; Young, Jacques; Laissue, Paul; Binart, Nadine; Beau, Isabelle

doi:10.1038/s41436-018-0287-y

Cited by 63 publications

(35 citation statements)

References 36 publications

(52 reference statements)

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“…In keeping with this, all reported lists have a varied capture of POI genes, and there has been only a modest success using panels for the genetic analysis of patients with POI. Recognizing the shortcomings of stringent criteria for analysis, WES data from published POI cohorts have been reanalyzed to identify previously missed diagnoses in KHDRBS1 , ATG7 , and ATG9A (Delcour et al, ; Wang et al, ). Our gene list contained 482 genes which had a predicted role in POI based on known variants in human cases, relevant phenotypes in mice with gene disruption, genetic associations in POI cohorts, and/or in vitro studies (File S1).…”

Section: Variants Of Interestmentioning

confidence: 99%

TP63‐truncating variants cause isolated premature ovarian insufficiency

et al. 2019

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Premature ovarian insufficiency involves amenorrhea and elevated follicle‐stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole‐exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63‐related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.

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Section: Variants Of Interestmentioning

confidence: 99%

TP63‐truncating variants cause isolated premature ovarian insufficiency

et al. 2019

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“…Indeed, although using specific tools (e.g., SIFT, Polyphen2) for filtering variants is an efficient method for proposing candidates from large amounts of data, they have been related to false negative results. We have used this methodology in two previous studies, one of which led a first description of functional mutations in ATG (autophagy) genes leading to POI (Carlosama et al., , Delcour et al., ).…”

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confidence: 99%

Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology

et al. 2018

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Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcrip-

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“…Several studies have suggested the involvement of the autophagy process in the regulation of the ovarian reserve of primordial follicles. For example, autophagy is implicated in maintaining the primordial oocyte pool in murine newborns [11], and the induction of autophagy at birth seems to be a crucial step to preserve the stock of primordial follicles [12,13].…”

Section: Follicular Ovarian Reserve and Its Regulationmentioning

confidence: 99%

The Impact of Chemotherapy on the Ovaries: Molecular Aspects and the Prevention of Ovarian Damage

Sonigo

Beau

Binart

et al. 2019

IJMS

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Cancer treatment, such as chemotherapy, induces early ovarian follicular depletion and subsequent infertility. In order to protect gametes from the gonadotoxic effects of chemotherapy, several fertility preservation techniques—such as oocyte or embryo cryopreservation with or without ovarian stimulation, or cryopreservation of the ovarian cortex—should be considered. However, these methods may be difficult to perform, and the future use of cryopreserved germ cells remains uncertain. Therefore, improving the methods currently available and developing new strategies to preserve fertility represent major challenges in the area of oncofertility. Animal and ovarian culture models have been used to decipher the effects of different cytotoxic agents on ovarian function and several theories regarding chemotherapy gonadotoxicity have been raised. For example, cytotoxic agents might (i) have a direct detrimental effect on the DNA of primordial follicles constituting the ovarian reserve and induce apoptosis; (ii) induce a massive growth of dormant follicles, which are then destroyed; or (ii) induce vascular ovarian damage. Thanks to improvements in the understanding of the mechanisms involved, a large number of studies have been carried out to develop molecules limiting the negative impact of chemotherapy on the ovaries.

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ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure

Abstract: Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.

Cited by 63 publications

References 36 publications

TP63‐truncating variants cause isolated premature ovarian insufficiency

TP63‐truncating variants cause isolated premature ovarian insufficiency

Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology

The Impact of Chemotherapy on the Ovaries: Molecular Aspects and the Prevention of Ovarian Damage

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