Disruption of the human cystin-1 myristoyl-electrostatic switch causes polycystic kidney disease that phenocopies autosomal recessive polycystic kidney disease - PubMed
11 hours ago
- #polycystic kidney disease
- #cystin-1
- #myristoyl-electrostatic switch
- Disruption of the human cystin-1 myristoyl-electrostatic switch causes polycystic kidney disease (PKD) resembling autosomal recessive PKD (ARPKD).
- CYS1 pathogenic variants (homozygous deletion or p.Gly2Ser mutation) were identified in two families with ARPKD-like kidney lesions.
- The myristoyl-electrostatic switch, involving Gly2 and adjacent arginine-rich regions, regulates cystin-1 membrane binding and intracellular trafficking.
- Phosphorylation of serine-17 (S17) modulates cystin-1 localization, with PKA-dependent reduction in ciliary trafficking upon cAMP activation.
- CRISPR/Cas9-generated cystin-null cells or those expressing cystin-1G2S showed increased cyst formation in 3D culture.
- PPM1A phosphatase interacts with cystin-1, and its inhibition reduces S17 dephosphorylation.
- Cystin-1 deficiency phenocopies ARPKD, highlighting its role in PKD pathogenesis.