Harrison Benjamin A, Mizrahi-Powell Emma, Pappas John, Thomas Kristen, Vasishta Subrahmanya, Hebbar Shripad, Shukla Anju, Nayak Shalini S, Truong Tina K, Woroch Amy, Kharbutli Yara, Gelb Bruce D, Mintz Cassie S, Evrony Gilad D, Smogorzewska Agata
Laboratory of Genome Maintenance, The Rockefeller University, New York, New York, USA.
Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York, USA.
J Clin Invest. 2025 Apr 17;135(11). doi: 10.1172/JCI185126. eCollection 2025 Jun 2.
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.
范可尼贫血（FA）是一种罕见的遗传性疾病，其特征是在先前鉴定的22个基因（FANCA - FANCW）中的任何一个中存在功能丧失变异，这些基因编码参与DNA链间交联（ICL）修复的蛋白质。患者的表型各不相同，但可能包括发育异常、早发性全血细胞减少症以及易患血液系统和实体肿瘤。在此，我们描述了两个不相关的家族，这些家族有多次妊娠丢失，其后代出现严重的发育和血液学异常，导致子宫内或早年死亡。在两个家族的患病儿童中均鉴定出FAAP100的纯合功能丧失变异。FAAP100蛋白与FANCB和FANCL相关联，FANCL是负责FANCD2和FANCI单泛素化的E3泛素连接酶，这是FA途径功能所必需的。源自患者的细胞表现出与FA一致的表型。野生型FAAP100 cDNA的表达而非源自患者的变异体挽救了观察到的细胞表型。这确立了FAAP100缺陷是FA的一个病因，FAAP100获得了FANCX的别名。具有FAAP100功能丧失变异的个体广泛的发育畸形是先前描述的FA表型中最严重的之一，表明FA途径对人类发育至关重要。
