FANCG – Fanconi Anemia

Fanconi anemia (FA) is an autosomal recessive bone marrow failure syndrome characterized by chromosomal fragility, congenital anomalies, and cancer predisposition. The FANCG gene encodes a core complex component essential for DNA interstrand crosslink repair. Biallelic FANCG variants define complementation group G and lead to defective FANCD2 ubiquitination and hypersensitivity to DNA cross-linkers.

Genetic evidence for FANCG–FA is robust. In an international registry of 307 unrelated FA patients, 18 distinct FANCG pathogenic variants were identified, including splice, nonsense, and frameshift alleles, establishing a recessive inheritance pattern (PMID:12552564). Four FA-G patients were functionally subtyped by retroviral complementation and immunoblot analysis, confirming FANCG as the defective gene in these families (PMID:11438206).

The variant spectrum includes missense, splice-site, and frameshift mutations. A recurrent founder allele c.637_643del (p.Tyr213LysfsTer6) was present in 82% of FA patients of sub-Saharan African descent (PMID:15657175). Private mutations, such as c.1157C>G (p.Pro386Arg), have also been reported in consanguineous families, with segregation in sibships supporting pathogenicity.

Functional assays demonstrate that FANCG loss‐of‐function underlies FA-G. Patient‐derived FANCG missense and truncating alleles fail to rescue mitomycin C hypersensitivity in FA-G cell lines and disrupt assembly of the FANCA–FANCG–FANCC complex (PMID:11093276). Phosphorylation of FANCG at Ser7 and Ser387 by cell cycle kinases is required for chromatin localization and complementation, highlighting post-translational regulation (PMID:15299017; PMID:15367677).

Animal and cellular models corroborate the mechanism. FANCG-deficient chickens (DT40) exhibit a nine-fold reduction in homologous recombination and hypersensitivity to cross-linkers, linking FANCG function to DNA double-strand break repair (PMID:12861027). Mesenchymal stromal cells from FA patients with FANCG mutations show accelerated senescence and dysregulated hematopoietic support, mirroring clinical bone marrow failure (PMID:36481320).

No credible reports dispute the association; all studies consistently confirm biallelic FANCG pathogenic variants in FA-G. Future work may further quantify genotype–phenotype correlations and refine therapeutic strategies targeting the FA pathway.

Key Take-home: FANCG is definitively implicated in autosomal recessive Fanconi anemia via loss-of-function variants that abolish DNA repair complex assembly, enabling precise genetic diagnosis and informing clinical management.

References

• Human mutation • 2003 • Spectrum of sequence variation in the FANCG gene: an International Fanconi Anemia Registry (IFAR) study. PMID:12552564
• Experimental hematology • 2001 • Functional analysis of patient-derived mutations in the Fanconi anemia gene, FANCG/XRCC9. PMID:11438206
• Blood • 2005 • A common Fanconi anemia mutation in black populations of sub-Saharan Africa. PMID:15657175
• European journal of human genetics • 2000 • Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9. PMID:11093276
• The Journal of biological chemistry • 2004 • Phosphorylation of fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway. PMID:15299017
• Molecular and cellular biology • 2004 • FANCG is phosphorylated at serines 383 and 387 during mitosis. PMID:15367677
• Molecular and cellular biology • 2003 • Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells. PMID:12861027
• Cytotherapy • 2023 • Mesenchymal stem/stromal cells from a transplanted, asymptomatic patient with Fanconi anemia exhibit an aging-like phenotype... PMID:36481320

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