FANCC – Fanconi Anemia

FANCC encodes the complementation group C protein in the Fanconi anemia DNA repair pathway. Biallelic pathogenic variants in FANCC cause Fanconi anemia (FA), an autosomal recessive disorder marked by congenital anomalies, progressive bone marrow failure, and cancer predisposition.

Inheritance of FANCC-related FA is autosomal recessive. A Dutch–Mennonite founder mutation, c.67delG (p.Asp23IlefsTer23), segregated with disease in 2 affected siblings among 13 family members tested (PMID:31044565). Segregation analysis across multiple families confirms that FANCC variants track with FA phenotypes.

Over 24 unique FANCC variants have been reported, including nonsense, frameshift, and splice-site changes such as c.456+4A>T (IVS4+4A>T) and c.553C>T (p.Arg185Ter) in diverse populations (PMID:8128956, PMID:7689011). The IVS4+4A>T splice mutation is prevalent in Ashkenazi Jews, whereas c.67delG arose in Mennonite and Dutch communities. Functional concordance of these variants supports their pathogenicity.

Cellular assays demonstrate that FANCC loss impairs resistance to DNA cross-linking agents. The FRP-50 truncated isoform from delG322 retains partial activity, correlating with milder clinical presentations (PMID:8639804). FANCC forms a nuclear complex with FANCA, essential for chromosomal breakage repair (PMID:9398857).

FANCC also modulates cytokine-induced JAK/STAT signaling and apoptosis. FA-C hematopoietic progenitors show hypersensitivity to IFN-γ via exaggerated Fas-mediated apoptosis, which is rescued by wild-type FANCC (PMID:9242526). These data elucidate distinct DNA repair and signaling roles of FANCC.

Integration of genetic and experimental findings over >30 years establishes a definitive gene–disease relationship. FANCC testing is critical for FA diagnosis, carrier screening, and prenatal counseling. Key take-home: Biallelic FANCC variants unequivocally cause FA, guiding clinical management and therapeutic strategies.

References

• Molecular genetics & genomic medicine | 2019 | FANCC Dutch founder mutation in a Mennonite family from Tamaulipas, México PMID:31044565
• American journal of human genetics | 1994 | Mutation analysis of the Fanconi anemia gene FACC. PMID:8128956
• Blood | 1996 | Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity. PMID:8639804
• Nature genetics | 1997 | The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. PMID:9398857
• Blood | 1997 | Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells. PMID:9242526

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