ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

Area of Science:

• Genetics
• Molecular Biology
• DNA Repair

Background:

• ERCC1-XPF endonuclease is crucial for nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair.
• Previous reports documented only two patients with bi-allelic ERCC1 mutations, both exhibiting Cockayne syndrome and succumbing in infancy.

Purpose of the Study:

• To characterize a novel presentation of ERCC1 deficiency in two siblings with bi-allelic mutations, extending the known clinical spectrum.
• To investigate the molecular mechanisms underlying the observed DNA repair deficiencies and clinical phenotype.

Main Methods:

• Genomic sequencing to identify ERCC1 mutations.
• Analysis of patient-derived fibroblasts and knock-in cells to assess ERCC1/XPF protein levels, protein interactions, and DNA repair capacity.
• Evaluation of cellular responses to DNA cross-linkers and DNA damaging agents.

Main Results:

• Two siblings identified with a deletion and a missense ERCC1 variant (R156W), leading to reduced ERCC1 and XPF protein levels.
• Mutant ERCC1 exhibited impaired interactions with NER and ICL repair proteins, resulting in diminished DNA damage recruitment.
• Patient cells displayed significantly reduced NER activity, increased chromosome breakage upon cross-linker exposure, and relatively normal DSB repair.

Conclusions:

• This study reports a new ERCC1 deficiency case with severe NER and ICL repair defects, presenting a unique phenotype in teenage patients.
• The findings highlight the critical role of ERCC1 in maintaining genomic stability and underscore the diverse clinical manifestations of ERCC1-related disorders.