Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signaling.

Abstract

Ciliopathies form a group of inherited disorders sharing several clinical manifestations because of abnormal cilia formation or function, and few treatments have been successful against these disorders. Here, we report a mouse model with mutated Sclt1 gene, which encodes a centriole distal appendage protein important for ciliogenesis. Sodium channel and clathrin linker 1 (SCLT1) mutations were associated with the oral-facial-digital syndrome (OFD), an autosomal recessive ciliopathy. The Sclt1-/- mice exhibit typical ciliopathy phenotypes, including cystic kidney, cleft palate and polydactyly. Sclt1-loss decreases the number of cilia in kidney; increases proliferation and apoptosis of renal tubule epithelial cells; elevates protein kinase A, extracellular signal-regulated kinases, SMAD and signal transducer and activator of transcription 3 (STAT3) pathways; and enhances pro-inflammation and pro-fibrosis pathways with disease progression. Embryonic kidney cyst formation of Sclt1-/- mice was effectively reduced by an anti-STAT3 treatment using pyrimethamine. Overall, we reported a new mouse model for the OFD; and our data suggest that STAT3 inhibition may be a promising treatment for SCLT1-associated cystic kidney.

• Authors: Jianshuang Li, Di Lu, Huadie Liu, Bart O Williams, Paul A Overbeek, Brendan Lee, Ling Zheng, Tao Yang
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 26 Issue 15 Pg. 2949-2960 (08 01 2017) ISSN: 1460-2083 [Electronic] England
• PMID: 28486600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• SCLT1 protein, human
• STAT3 Transcription Factor
• Sodium Channels
• Stat3 protein, mouse
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cilia (metabolism)
• Ciliopathies (genetics, metabolism)
• Cysts (metabolism)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Kidney (metabolism)
• Kidney Diseases, Cystic (etiology, genetics, metabolism)
• MAP Kinase Signaling System
• Mice
• Mice, Transgenic
• Models, Animal
• Mutation
• Phenotype
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction
• Sodium Channels (genetics, metabolism)