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

Clémence Delcour; Larbi Amazit; Liliana C Patino; Françoise Magnin; Jérôme Fagart; Brigitte Delemer; Jacques Young; Paul Laissue; Nadine Binart; Isabelle Beau

doi:10.1038/s41436-018-0287-y

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

Clémence Delcour, Larbi Amazit, Liliana C Patino, Françoise Magnin, Jérôme Fagart, Brigitte Delemer, Jacques Young, Paul Laissue, Nadine Binart, Isabelle Beau

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

PURPOSE: Primary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.

METHODS: We have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3β (LC3), were then used to link these genes to this lysosomal degradation pathway.

RESULTS: We venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.

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

Translated title of the contribution	Mutaciones pérdida de función en ATG7 y ATG9A contribuyen con la disfunción en la autofagia y conducen a POI
Original language	English
Article number	21
Pages (from-to)	930–938
Number of pages	8
Journal	Genetics in Medicine
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/s41436-018-0287-y
State	Published - Apr 17 2019

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@article{6141d69125d740a0918879045ed212f0,

title = "ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure",

abstract = "PurposePrimary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.MethodsWe have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3β (LC3), were then used to link these genes to this lysosomal degradation pathway.ResultsWe venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.ConclusionOur results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.",

author = "Cl{\'e}mence Delcour and Larbi Amazit and Patino, {Liliana C} and Fran{\c c}oise Magnin and J{\'e}r{\^o}me Fagart and Brigitte Delemer and Jacques Young and Paul Laissue and Nadine Binart and Isabelle Beau",

year = "2019",

month = apr,

day = "17",

doi = "10.1038/s41436-018-0287-y",

language = "Ingl{\'e}s",

volume = "21",

pages = "930–938",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure

AU - Delcour, Clémence

AU - Amazit, Larbi

AU - Patino, Liliana C

AU - Magnin, Françoise

AU - Fagart, Jérôme

AU - Delemer, Brigitte

AU - Young, Jacques

AU - Laissue, Paul

AU - Binart, Nadine

AU - Beau, Isabelle

PY - 2019/4/17

Y1 - 2019/4/17

N2 - PurposePrimary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.MethodsWe have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3β (LC3), were then used to link these genes to this lysosomal degradation pathway.ResultsWe venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.ConclusionOur results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.

AB - PurposePrimary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.MethodsWe have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3β (LC3), were then used to link these genes to this lysosomal degradation pathway.ResultsWe venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.ConclusionOur results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.

U2 - 10.1038/s41436-018-0287-y

DO - 10.1038/s41436-018-0287-y

M3 - Artículo

C2 - 30224786

SN - 1098-3600

VL - 21

SP - 930

EP - 938

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 4

M1 - 21

ER -

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

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