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

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 3? (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. © 2018, American College of Medical Genetics and Genomics.

• Fecha de publicación: 2019
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/24148
• Acceso en línea: https://doi.org/10.1038/s41436-018-0287-y; https://repository.urosario.edu.co/handle/10336/24148
• Palabra clave: Autophagy related protein 7; Atg7 protein, human; Atg9a protein, human; Autophagy related protein; Autophagy related protein 7; Follitropin; Membrane protein; Vesicular transport protein; Article; Atg7 gene; Atg9a gene; Autophagosome; Autophagy; Computer model; Controlled study; Female; Gene; Gene identification; Gene location; Gene sequence; Genetic variability; Haploinsufficiency; Human; Human cell; Loss of function mutation; Major clinical study; Mutational analysis; Ovarian reserve; Ovary insufficiency; Pathogenesis; Whole exome sequencing; Adult; Autophagy; Early menopause; Genetic predisposition; Genetics; Loss of function mutation; Pathology; Premature ovarian failure; Adult; Autophagy; Autophagy-related protein 7; Autophagy-related proteins; Female; Follicle stimulating hormone; Genetic predisposition to disease; Humans; Loss of function mutation; Membrane proteins; Primary ovarian insufficiency; Vesicular transport proteins; Whole exome sequencing; Autophagy; Infertility; Ovarian reserve; premature; Menopause
• License: Abierto (Texto Completo)