CSH1 and Cockayne syndrome

Cockayne syndrome (CS) is an autosomal recessive disorder characterized by growth delay, photosensitivity, and neurodevelopmental abnormalities. Multiple independent studies have implicated CSH1 in CS, with evidence emerging from family-based segregation analyses and case studies across diverse populations (PMID:15211661).

Genetic findings include the identification of various variant types such as splice site alterations and frameshift deletions. In one study, a kindred with CS was found to harbor multiple abnormal splicing variants of the CSA gene (CSH1), establishing a mechanistic link between aberrant mRNA processing and the CS phenotype (PMID:15211661).

Case reports have documented autosomal recessive inheritance, with affected probands presenting with features like growth delay, failure to thrive, and global developmental delay. One notable variant is c.394_398delTTACA (p.Leu132ProfsTer), identified in a Chinese patient, which adds to the mutation spectrum observed in CS (PMID:26173784).

Segregation studies in multiple families further strengthen the gene-disease association by demonstrating concordant transmission of pathogenic variants among affected relatives. The recurrence of diverse variant classes, including those affecting splicing and causing frameshifts, lends robust support to the causal implication of CSH1 in Cockayne syndrome.

Functional studies complement the genetic evidence by revealing that mutant CSH1 products lead to impaired transcription-coupled repair and reduced ATPase activity in cellular models. These experimental findings are consistent with the clinical features of CS and underscore the impact of altered CSH1 function on cellular homeostasis (PMID:9565609, PMID:12560492).

In summary, the integration of genetic and functional data establishes a strong association between CSH1 and Cockayne syndrome. This evidence supports the use of CSH1 as a reliable diagnostic marker in clinical settings and provides a foundation for future therapeutic development.

References

• American journal of medical genetics. Part A • 2004 • A kindred with Cockayne syndrome caused by multiple splicing variants of the CSA gene PMID:15211661
• Proceedings of the National Academy of Sciences • 2009 • A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage PMID:19329487
• Pediatric neurology • 2015 • Two Novel Heterozygous Mutations in ERCC8 Cause Cockayne Syndrome in a Chinese Patient PMID:26173784
• The Journal of biological chemistry • 1998 • Biochemical and biological characterization of wild-type and ATPase-deficient Cockayne syndrome B repair protein PMID:9565609
• Nucleic acids research • 2003 • Functional consequences of mutations in the conserved SF2 motifs and post-translational phosphorylation of the CSB protein PMID:12560492

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