Abstract
Background: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (ERCC6) gene that encodes the CS group B (CSB) protein. Using whole exome sequencing, we recently identified a novel homozygous missense mutation (Leu536Trp) in CSB in a Taiwanese boy with CS. Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. Methods: We used iterative threading assembly refinement (I-TASSER) to generate a predictive 3D structure of CSB. We calculated the change of mutation energy after residues substitution on the protein stability using I-TASSER as well as the artificial intelligence program Alphafold. Results: The Asp532Gly variant destabilized both modeled structures, while the Leu536Trp variant showed no effect on I-TASSER’s model but destabilized the Alphafold’s modeled structure. Conclusions: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. Furthermore, we suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability.
Highlights
Cockayne syndrome (CS; MIM# 133540, 216400), known as Neill–Dingwall syndrome, is a rare autosomal recessive neurodegenerative disorder that is characterized by progressive growth failure, microcephaly, global developmental delay, cutaneous photosensitivity, and premature pathological aging [1]
The ACMG defines this missense mutation in excision repair crosscomplementing protein group 6 (ERCC6) as “likely pathogenic”, according to the interpretation from the Varsome database. This mutation has not been listed as a pathogenic variant in CS group B (CSB) by ClinVar Miner, which was updated on 31 July 2021
The Leu536Trp mutation showed destabilizing effects in the Alphfold model (Table 1). We suggest that this missense mutation c.1607T>G (p.Leu536Trp) in the ERCC6 gene is a “pathogenic” mutation and this homozygous form presents in the CSB case examined here
Summary
Cockayne syndrome (CS; MIM# 133540, 216400), known as Neill–Dingwall syndrome, is a rare autosomal recessive neurodegenerative disorder that is characterized by progressive growth failure, microcephaly, global developmental delay, cutaneous photosensitivity, and premature pathological aging [1]. The ERCC6 gene encodes a protein of 1493 amino acids with seven ATPase motifs known as CSB [4]. This protein belongs to the SWI2/SNF2 family and is engaged in nucleotide excision repair (NER) as well as base excision repair (BER). Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. Conclusions: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. We suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability
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