Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis.

Key Points: Ketogenic diet can change the metabolism in the body and helped restore the function of altered pathways in nephropathic cystinosis. Ketogenic diet had significant benefits for preventing kidney damage, even when initiated after the onset of kidney impairment. Ketogenic diet may provide a partial therapeutic alternative in countries where cysteamine therapy is too expensive.

Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization.

Differentiation is critical for cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions.

Multisystem involvement, defective lysosomes and impaired autophagy in a novel rat model of nephropathic cystinosis.

Recessive mutations in the CTNS gene encoding the lysosomal transporter cystinosin cause cystinosis, a lysosomal storage disease leading to kidney failure and multisystem manifestations. A Ctns knockout mouse model recapitulates features of cystinosis, but the delayed onset of kidney manifestations, phenotype variability and strain effects limit its use for mechanistic and drug development studies. To provide a better model for cystinosis, we generated a Ctns knockout rat model using CRISPR/Cas9 technology.

Six1 proteins with human branchio-oto-renal mutations differentially affect cranial gene expression and otic development.

Single-nucleotide mutations in human result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of branchio-otic (BOS) and branchio-oto-renal (BOR) cases. The phenotypic variation between patients with the same mutation, even within affected members of the same family, make it difficult to functionally distinguish between the different mutations. We made four of the BOS/BOR substitutions in the Six1 protein (V17E, R110W, W122R, Y129C), which is 100% identical to human in both the protein-protein interaction domain and the homeodomain, and expressed them in embryos to determine whether they cause differential changes in early craniofacial gene expression, otic gene expression or otic morphology.

Pa2G4 is a novel Six1 co-factor that is required for neural crest and otic development.

Mutations in SIX1 and in its co-factor, EYA1, underlie Branchiootorenal Spectrum disorder (BOS), which is characterized by variable branchial arch, otic and kidney malformations. However, mutations in these two genes are identified in only half of patients. We screened for other potential co-factors, and herein characterize one of them, Pa2G4 (aka Ebp1/Plfap).