Deficiency of the Fanconi anemia core complex protein FAAP100 results in severe Fanconi anemia.

TitleDeficiency of the Fanconi anemia core complex protein FAAP100 results in severe Fanconi anemia.
Publication TypeJournal Article
Year of Publication2025
AuthorsHarrison BA, Mizrahi-Powell E, Pappas J, Thomas K, Vasishta S, Hebbar S, Shukla A, Nayak SS, Truong TK, Woroch A, Kharbutli Y, Gelb BD, Mintz CS, Evrony GD, Smogorzewska A
JournalJ Clin Invest
Volume135
Issue11
Date Published2025 Jun 02
ISSN1558-8238
KeywordsChild, Child, Preschool, Fanconi Anemia, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia Complementation Group L Protein, Fanconi Anemia Complementation Group Proteins, Female, Humans, Infant, Loss of Function Mutation, Male, Pedigree, Pregnancy
Abstract

Fanconi anemia (FA) is a rare genetic disease characterized by loss-of-function variants in any of the 22 previously identified genes (FANCA-FANCW) that encode proteins participating in the repair of DNA interstrand crosslinks (ICLs). Patient phenotypes are variable but may include developmental abnormalities, early-onset pancytopenia, and a predisposition to hematologic and solid tumors. Here, we describe 2 unrelated families with multiple pregnancy losses and offspring presenting with severe developmental and hematologic abnormalities leading to death in utero or in early life. Homozygous loss-of-function variants in FAAP100 were identified in affected children of both families. The FAAP100 protein associates with FANCB and FANCL, the E3 ubiquitin ligase responsible for the monoubiquitination of FANCD2 and FANCI, which is necessary for FA pathway function. Patient-derived cells exhibited phenotypes consistent with FA. Expression of the WT FAAP100 cDNA, but not the patient-derived variants, rescued the observed cellular phenotypes. This establishes FAAP100 deficiency as a cause of FA, with FAAP100 gaining an alias as FANCX. The extensive developmental malformations of individuals with FAAP100 loss-of-function variants are among the most severe across previously described FA phenotypes, indicating that the FA pathway is essential for human development.

DOI10.1172/JCI185126
Alternate JournalJ Clin Invest
PubMed ID40244696
PubMed Central IDPMC12126221
Grant ListR01 GM140400 / GM / NIGMS NIH HHS / United States
T32 GM152349 / GM / NIGMS NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States

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