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ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure
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...
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| Published in: | Genetics in medicine 2019-04, Vol.21 (4), p.930-938 |
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| container_end_page | 938 |
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| container_title | Genetics in medicine |
| container_volume | 21 |
| creator | Delcour, Clémence Amazit, Larbi Patino, Liliana C Magnin, Françoise Fagart, Jérôme Delemer, Brigitte Young, Jacques Laissue, Paul Binart, Nadine Beau, Isabelle |
| description | 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.
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.
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.
Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI. |
| doi_str_mv | 10.1038/s41436-018-0287-y |
| format | article |
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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.
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.
Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.</description><identifier>ISSN: 1098-3600</identifier><identifier>EISSN: 1530-0366</identifier><identifier>DOI: 10.1038/s41436-018-0287-y</identifier><identifier>PMID: 30224786</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Adult ; Autophagy ; Autophagy - genetics ; Autophagy-Related Protein 7 - genetics ; Autophagy-Related Proteins - genetics ; Endocrinology and metabolism ; Exome Sequencing ; Female ; Follicle Stimulating Hormone - genetics ; Genetic Predisposition to Disease ; Human health and pathology ; Humans ; Life Sciences ; Loss of Function Mutation - genetics ; Membrane Proteins - genetics ; Menopause, Premature - genetics ; Primary Ovarian Insufficiency - genetics ; Primary Ovarian Insufficiency - pathology ; Vesicular Transport Proteins - genetics</subject><ispartof>Genetics in medicine, 2019-04, Vol.21 (4), p.930-938</ispartof><rights>Copyright Nature Publishing Group Apr 2019</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c472t-360036954abd00ff26feabc0befe4bebeb634811be7d77a4fe739c7686bf36223</citedby><orcidid>0000-0002-3352-6813</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30224786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.univ-reims.fr/hal-04319232$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Delcour, Clémence</creatorcontrib><creatorcontrib>Amazit, Larbi</creatorcontrib><creatorcontrib>Patino, Liliana C</creatorcontrib><creatorcontrib>Magnin, Françoise</creatorcontrib><creatorcontrib>Fagart, Jérôme</creatorcontrib><creatorcontrib>Delemer, Brigitte</creatorcontrib><creatorcontrib>Young, Jacques</creatorcontrib><creatorcontrib>Laissue, Paul</creatorcontrib><creatorcontrib>Binart, Nadine</creatorcontrib><creatorcontrib>Beau, Isabelle</creatorcontrib><title>ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure</title><title>Genetics in medicine</title><addtitle>Genet Med</addtitle><description>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.
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.
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.
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Amazit, Larbi ; Patino, Liliana C ; Magnin, Françoise ; Fagart, Jérôme ; Delemer, Brigitte ; Young, Jacques ; Laissue, Paul ; Binart, Nadine ; Beau, Isabelle</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c472t-360036954abd00ff26feabc0befe4bebeb634811be7d77a4fe739c7686bf36223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Autophagy</topic><topic>Autophagy - genetics</topic><topic>Autophagy-Related Protein 7 - genetics</topic><topic>Autophagy-Related Proteins - genetics</topic><topic>Endocrinology and metabolism</topic><topic>Exome Sequencing</topic><topic>Female</topic><topic>Follicle Stimulating Hormone - genetics</topic><topic>Genetic Predisposition to Disease</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Loss of Function Mutation - genetics</topic><topic>Membrane Proteins - genetics</topic><topic>Menopause, Premature - genetics</topic><topic>Primary Ovarian Insufficiency - genetics</topic><topic>Primary Ovarian Insufficiency - pathology</topic><topic>Vesicular Transport Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Delcour, Clémence</creatorcontrib><creatorcontrib>Amazit, Larbi</creatorcontrib><creatorcontrib>Patino, Liliana C</creatorcontrib><creatorcontrib>Magnin, Françoise</creatorcontrib><creatorcontrib>Fagart, Jérôme</creatorcontrib><creatorcontrib>Delemer, Brigitte</creatorcontrib><creatorcontrib>Young, Jacques</creatorcontrib><creatorcontrib>Laissue, Paul</creatorcontrib><creatorcontrib>Binart, Nadine</creatorcontrib><creatorcontrib>Beau, Isabelle</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest_Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Genetics in medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Delcour, Clémence</au><au>Amazit, Larbi</au><au>Patino, Liliana C</au><au>Magnin, Françoise</au><au>Fagart, Jérôme</au><au>Delemer, Brigitte</au><au>Young, Jacques</au><au>Laissue, Paul</au><au>Binart, Nadine</au><au>Beau, Isabelle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure</atitle><jtitle>Genetics in medicine</jtitle><addtitle>Genet Med</addtitle><date>2019-04</date><risdate>2019</risdate><volume>21</volume><issue>4</issue><spage>930</spage><epage>938</epage><pages>930-938</pages><issn>1098-3600</issn><eissn>1530-0366</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>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.
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.
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.
Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>30224786</pmid><doi>10.1038/s41436-018-0287-y</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-3352-6813</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Genetics in medicine, 2019-04, Vol.21 (4), p.930-938 |
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| source | ScienceDirect Journals |
| subjects | Adult Autophagy Autophagy - genetics Autophagy-Related Protein 7 - genetics Autophagy-Related Proteins - genetics Endocrinology and metabolism Exome Sequencing Female Follicle Stimulating Hormone - genetics Genetic Predisposition to Disease Human health and pathology Humans Life Sciences Loss of Function Mutation - genetics Membrane Proteins - genetics Menopause, Premature - genetics Primary Ovarian Insufficiency - genetics Primary Ovarian Insufficiency - pathology Vesicular Transport Proteins - genetics |
| title | ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure |
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