Another Fanconi anemia gene joins the club
Claire C. Homan, Hamish S. Scott, Parvathy Venugopal
Claire C. Homan, Hamish S. Scott, Parvathy Venugopal
View: Text | PDF
Commentary

Another Fanconi anemia gene joins the club

Abstract

Fanconi anemia (FA) is the most common inherited bone marrow failure disorder, caused by pathogenic variants in genes involved in the FA DNA repair pathway. In this issue of the JCI, two studies report three germline homozygous loss-of-function variants in FAAP100, a key component of the FA core complex, identified in three unrelated families. These variants result in severe developmental phenotypes that are among the most extreme reported in FA to date. Harrison et al. described individuals from two families with recurrent pregnancy loss and neonatal death due to homozygous FAAP100 frameshift and truncating variants, respectively. Kuehl et al. identified a homozygous missense variant in a fetus with congenital malformations consistent with FA. Collectively, both studies provide robust functional evidence from ex vivo and in vitro assays with animal models supporting the pathogenicity of these variants and establish FAAP100 as a causative FA gene.

Authors

Claire C. Homan, Hamish S. Scott, Parvathy Venugopal

×

Figure 1

Disruption of the FA/BRCA DNA repair pathway correlates with clinical phenotypes.

Options: View larger image (or click on image) Download as PowerPoint
Disruption of the FA/BRCA DNA repair pathway correlates with clinical ph...
The FA DNA repair pathway is essential for ICL repair. Upon encountering an ICL, replication forks stall, triggering pathway activation. Subsequently, the anchor complex — comprising FANCM, FAAP24, MHF1, and MHF2 — recognizes the ICL, recruiting the FA core complex to the chromatin. The core complex consists of three distinct subcomplexes: (a) the AG20 complex (FANCA, FANCG, and FAAP20), (b) the BL100/catalytic core complex (FANCB, FANCL, and FAAP100), and (c) the CEF subcomplex (FANCC, FANCE, and FANCF). Among these, the catalytic core complex is essential for E3 ubiquitin ligase activity of the complex. In coordination with FANCT, an E2 ubiquitin–conjugating enzyme, the core complex catalyzes the monoubiquitination of the ID2 complex, a pivotal activation event in the FA repair pathway, which can be regulated by the deubiquitinating enzymes USP1 and UAF1. The monoubiquitinated ID2 complex aids recruitment of structure-specific endonucleases, which mediate ICL unhooking through single-strand DNA cutting. Following unhooking, specialized translesion synthesis (TLS) polymerases perform bypass synthesis across the lesion, leading to the formation of a DNA double-strand break (DSB). This DSB is subsequently repaired through homologous recombination, restoring genomic integrity. Genotype-phenotype correlations of the FA syndrome corresponding to the FA complex genes are supported by strong cohort-based evidence but do not necessarily encompass all reported phenotypes due to clinical heterogeneity within each syndrome. VACTERL-H (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, esophageal or duodenal atresia, renal abnormalities, limb defects, and hydrocephalus); PHENOS (Pigmentation, small Head, small Eyes, Neurologic, Otologic, Short stature); MRN, complex including Mre11, Rad50, and Nbs1; Ub, ubiquitin.