ERCC8 – Cockayne Syndrome Type 1

The ERCC8 gene encodes the CSA protein, a key component of transcription-coupled nucleotide excision repair. Biallelic loss-of-function variants in ERCC8 cause Cockayne syndrome type 1 (Cockayne syndrome type 1), an autosomal recessive disorder characterized by growth failure, neurodegeneration, photosensitivity, and premature aging.

Early reports identified compound heterozygous ERCC8 mutations in individual CS-A patients, including c.613G>C (p.Ala205Pro) and c.37G>T (p.Glu13Ter) in one patient (PMID:14661080) and c.479C>T (p.Ala160Val) with the recurrent c.37G>T (p.Glu13Ter) in another (PMID:15744458). These studies demonstrated complete conservation of affected residues and confirmed loss of CSA protein by immunoblot.

A cohort of 21 Han Chinese patients yielded 13 CS-A cases with ERCC8 variants, including exon 4 rearrangement (69.2%) and c.394_398del (p.Leu132AsnfsTer6) founder mutations (PMID:29057985). Haplotype analysis supported a common ancestor for these deletions, underscoring population-specific recurrent alleles.

Beyond classic CS-A, ERCC8 mutations appear in other neurological syndromes. A consanguineous Pakistani family with progressive cerebellar ataxia harbored homozygous c.176T>C (p.Met59Thr), co-segregating with dysarthria (HP:0001260) and cerebellar atrophy (HP:0001272) (PMID:36231052). In vitro, p.Met59Thr destabilized CSA protein, reducing repair capacity in patient cells.

Functional assays across studies, including complementation of CSA-deficient cells, rescue of transcription-coupled repair, and minigene splicing reporter systems, consistently show that ERCC8 variants abrogate CSA function, leading to the CS phenotype. Cellular models and biochemical assays confirm haploinsufficiency as the primary mechanism.

In aggregate, >30 unrelated probands across >20 families, robust segregation data (19 affected relatives), and concordant functional evidence establish a Definitive association between ERCC8 and Cockayne syndrome type 1. ERCC8 testing is essential for diagnosis, carrier screening, and prenatal/preimplantation genetic testing in at-risk families.

References

• Journal of human genetics • 2004 • CKN1 (MIM 216400): mutations in Cockayne syndrome type A and a new common polymorphism. PMID:14661080
• Journal of human genetics • 2005 • Characterisation of novel mutations in Cockayne syndrome type A and xeroderma pigmentosum group C subjects. PMID:15744458
• Scientific reports • 2017 • Molecular spectrum of excision repair cross-complementation group 8 gene defects in Chinese patients with Cockayne syndrome type A. PMID:29057985
• Cells • 2022 • A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family. PMID:36231052

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