期刊
AGING-US
卷 14, 期 13, 页码 5299-5310出版社
IMPACT JOURNALS LLC
关键词
Cockayne syndrome; DNA excision repair; ERCC8; segmental progeroid disease
资金
- Vietnam Academy of Science and Technology [NVCC40.01/20-20]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [470092532]
- Japan Agency for Medical Research and Development (AMED) [JP21ek0109486, JP21ek0109549, JP21cm0106503, JP21ek0109493]
- JSPS KAKENHI [JP22H03047]
This study describes siblings with classical Cockayne syndrome but without photosensitivity, leading to a delayed diagnosis. Two novel compound heterozygous ERCC8 variants were identified and their causality was confirmed through experimental investigation. Structural modeling of one variant suggests an impact on protein-protein interaction.
Cockayne syndrome (CS) is a rare progeroid disorder characterized by growth failure, microcephaly, photosensitivity, and premature aging, mainly arising from biallelic ERCC8 (CS-A) or ERCC6 (CS-B) variants. In this study we describe siblings suffering from classical Cockayne syndrome but without photosensitivity, which delayed a clinical diagnosis for 16 years. By whole-exome sequencing we identified the two novel compound heterozygous ERCC8 variants c.370_371del (p.L124Efs*15) and c.484G>C (p.G162R). The causality of the ERCC8 variants, of which one results in a frameshift and the other affects the WD3 domain, was tested and confirmed by a rescue experiment investigating DNA repair in H2O2 treated patient fibroblasts. Structural modeling of the p.G162R variant indicates effects on protein-protein interaction. This case shows the importance to test for ERCC6 and ERCC8 variants even if patients do not present with a complete CS phenotype.
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