CYS1 – Polycystic Kidney Disease

CYS1 has been implicated as a minor autosomal recessive locus for polycystic kidney disease (PKD) (ARPKD subtype) within a cohort study of 9 PKD-associated genes (PMID:38097330). A limited number of unrelated probands with biallelic CYS1 variants have been reported, consistent with AR inheritance and early-onset cystic kidney disease.

Genetic evidence remains limited, with few case reports describing recessive CYS1 variants in patients presenting with ARPKD-like phenotypes (PMID:38097330). No large pedigrees demonstrate extensive segregation to date. Variant spectrum data are sparse and no recurrent or founder alleles have been established.

Functional studies in the cpk mouse model demonstrate that loss of cystin (Cys1) leads to post-translational loss of fibrocystin (FPC), disruption of primary cilium architecture, and altered proteome integrity via defective E3 ubiquitin ligase complexes, recapitulating human ARPKD pathology (PMID:37318790). Complementary cell-based assays confirm cystin-dependent regulation of FPC levels through selective autophagy.

Additional mechanistic work shows that the transcription factor TFAP2B binds and activates the Cys1 promoter in renal collecting duct cells, suggesting a regulatory network essential for renal tubular differentiation; disruption leads to ductal dilatation akin to ARPKD (PMID:36710876).

Together, limited clinical case data and concordant in vivo and in vitro functional assays support a pathogenic role for CYS1 in ARPKD. Further identification of independent families and detailed segregation analyses will strengthen the genetic evidence.

Key take-home: CYS1 should be included in comprehensive ARPKD gene panels, as functional data robustly implicate cystin deficiency in cystogenesis.

References

• Advances in kidney disease and health • 2023 • Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes. PMID:38097330
• FASEB journal : official publication of the Federation of American Societies for Experimental Biology • 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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