FANCL gene mutations in premature ovarian insufficiency. Issue 5 (24th February 2020)

• Record Type: Journal Article
• Authors: Yang, Yajuan; Guo, Ting; Liu, Ran; Ke, Hanni; Xu, Weiwei; Zhao, Shidou; Qin, Yingying
• Is Part Of: Human mutation. Volume 41:Issue 5(2020)
• Page Start: 1033
• Page End: 1041
• Publication Date: 2020-02-24
• Subjects: DNA repair -- FANCL -- mutation -- premature ovarian insufficiency; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23997
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: The Fanconi anemia (FA) pathway is mainly involved in DNA interstrand crosslinks (ICLs) repair in the genome. Several FA genes, including FANCD1/BRCA2, FANCM, and FANCU/XRCC2, have been identified as causative genes for premature ovary insufficiency (POI). Fanconi anemia group L protein (FANCL) cooperates with FANCT/UBE2T to ubiquitinate the FANCI‐D2 dimer, which is a crucial event in the process of ICLs repair. Fancl‐ knockout mice phenocopy human POI, but the role of FANCL mutations in POI pathogenesis has not been confirmed. In the present work, potentially pathogenic mutations in the FANCL gene were screened in 200 Chinese patients with idiopathic POI and in 200 matched controls. Two novel heterozygous frameshift mutations, c.1048_1051delGTCT (p.Gln350Valfs*18) and c.739dupA (p.Met247Asnfs*4), were identified in the FANCL gene in POI patients but not in controls. Wild‐type FANCL protein was predominantly localized in the nuclei, while both mutant FANCL proteins were retained in the cytoplasm. In addition, the FANCL variants exhibited impaired ubiquitin‐ligase activity and compromised DNA repair ability after mitomycin C treatment. Furthermore, the FANCL variants were deleterious and might be associated with haploinsufficiency. Our results show that FANCL mutations are potentially causative for POI by disrupting DNA damage repair processes. Abstract : FANCL mutations cause premature ovary insufficiency by disrupting DNA repair.