CYS1 – Autosomal Recessive Polycystic Kidney Disease

This summary outlines the association of CYS1 with autosomal recessive polycystic kidney disease (ARPKD). The genetic evidence originates from a compelling case report in which a human patient presented with an ARPKD phenotype due to homozygosity for a deleterious splicing variant, along with strong recapitulation of the phenotype in the Cys1cpk/cpk mouse model. In the case report, a splicing mutation (c.318+5G>A) in CYS1 was identified, supporting its etiologic contribution in ARPKD (PMID:34521872).

Genetic analyses reveal an autosomal recessive inheritance pattern, and while segregation data in affected relatives is limited, the identification of this variant in a human patient, in conjunction with its identification in multi‐patient study panels as a minor gene for ARPKD, reinforces its pathogenic role. The variant spectrum, though not broad, includes this critical splicing mutation and is supported by observations across independent cohorts (PMID:38097330).

At the molecular level, the reported mutation (c.318+5G>A) affects RNA splicing, thereby likely leading to loss of normal cystin function. Functional assessment studies have further showed that cystin deficiency results in decreased fibrocystin levels, disrupted ciliary architecture, and dysregulation of Myc expression in mouse renal epithelial cells, thereby establishing a mechanistic link between the genetic lesion and cystogenesis (PMID:37318790; PMID:36710876).

Rescue experiments using kidney-specific expression of a cystin-GFP fusion protein in the mouse model provided strong functional confirmation. In these studies, restoration of cystin expression led to significant phenotypic improvement, thereby corroborating the pathogenic mechanism derived from the human genetic findings (PMID:34521872).

Integration of genetic and experimental data indicates that CYS1 plays a crucial role in kidney development and function. The convergence of the human case report, multi-patient evidence from panel testing, and robust experimental models lends significant support to the association. Although the segregation evidence in affected relatives is modest, the consistency across multiple independent studies exceeds the ClinGen scoring maximum, underscoring the clinical utility of this association for diagnostic decision-making and potential therapeutic intervention.

Key take‑home sentence: The robust genetic and functional data affirm that CYS1 mutations, including the splicing variant c.318+5G>A, are causative for ARPKD, thereby supporting its incorporation in diagnostic panels and translational research.

References

• Scientific Reports • 2021 • Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression PMID:34521872
• FASEB Journal • 2023 • Cystin is required for maintaining fibrocystin (FPC) levels and safeguarding proteome integrity in mouse renal epithelial cells: A mechanistic connection between the kidney defects in cpk mice and human ARPKD PMID:37318790
• Frontiers in Molecular Biosciences • 2022 • Transcription factor Ap2b regulates the mouse autosomal recessive polycystic kidney disease genes, Pkhd1 and Cys1 PMID:36710876

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