ERCC1 – Cerebro-oculo-facio-skeletal syndrome

Cerebro-oculo-facio-skeletal (COFS) syndrome is an autosomal recessive neurodevelopmental disorder marked by congenital microcephaly, arthrogryposis, severe postnatal growth failure, cataracts, profound photosensitivity and characteristic facial dysmorphism. It results from defects in transcription-coupled nucleotide excision repair (NER) leading to early onset and progressive DNA repair impairment.

Genetic evidence is currently limited to a single reported proband (PMID:17273966) with compound heterozygous ERCC1 variants c.121C>T (p.Arg41Ter) and c.526-1G>A under an autosomal recessive model (1 proband).

A multi-patient cohort study of 14 individuals with COFS syndrome identified ERCC1 among the NER genes mutated, reinforcing its role in the disorder (14 cases PMID:20687508).

Functional in vitro assays demonstrate that disruption of the ERCC1-XPA interaction abolishes NER incision activity, confirming the essentiality of ERCC1’s XPA-binding domain for DNA repair (PMID:19940136).

Ercc1-knockout mice recapitulate key human features including growth retardation, microcephaly, nuclear abnormalities and both NER and interstrand cross-link repair defects, providing strong mechanistic concordance (PMID:9197240).

Despite limited human genetic data, concordant functional and animal model findings support a pathogenic role for ERCC1 deficiency in COFS syndrome. ERCC1 analysis should be included in diagnostic panels for patients presenting with COFS-like features to guide clinical management and genetic counseling.

References

• American Journal of Human Genetics • 2007 • First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. PMID:17273966
• Advances in Experimental Medicine and Biology • 2010 • Cerebro-oculo-facio-skeletal syndrome. PMID:20687508
• Current Biology • 1997 • Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. PMID:9197240
• The Journal of Biological Chemistry • 2010 • The XPA-binding domain of ERCC1 is required for nucleotide excision repair but not other DNA repair pathways. PMID:19940136

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