ERCC4 – Fanconi anemia complementation group Q

ERCC4 encodes the structure-specific endonuclease XPF, which partners with ERCC1 to execute key incisions during nucleotide excision repair and interstrand crosslink (ICL) repair. Biallelic pathogenic variants in ERCC4 cause autosomal recessive Fanconi anemia complementation group Q (Fanconi anemia complementation group Q), characterized by progressive bone marrow failure and cancer predisposition.

Genetic evidence includes two unrelated probands with compound heterozygous ERCC4 variants (PMID:23623386). Four distinct pathogenic variants have been reported: three missense and one frameshift change. A representative allele is c.689T>C (p.Leu230Pro), identified in trans with a truncating mutation in both probands (PMID:23623386). Segregation analysis confirmed autosomal recessive inheritance, with each parent heterozygous for a single ERCC4 allele.

Functional studies demonstrated that wild-type ERCC4 cDNA rescues the chromosomal instability and ICL repair defects in patient-derived cell lines, while nucleotide excision repair capacity remains largely intact (PMID:23623386). Biochemical assays revealed that the identified FA-causing ERCC4 mutations severely disrupt XPF endonuclease activity in ICL repair but spare UV-induced excision repair, underscoring a separation-of-function mechanism.

Collectively, the concordant genetic and experimental data support a strong gene–disease relationship between ERCC4 and Fanconi anemia complementation group Q. ERCC4 should be included in diagnostic gene panels for Fanconi anemia, and variant interpretation should consider both ICL and NER impacts. Key take-home: Biallelic ERCC4 mutations underlie FANCQ by selectively impairing interstrand crosslink repair, guiding targeted genetic testing and therapy.

References

• American Journal of Human Genetics • 2013 • Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia PMID:23623386

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