Advertisement

 

 

Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction.

Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction.
Author Information (click to view)

Elmonem MA, Khalil R, Khodaparast L, Khodaparast L, Arcolino FO, Morgan J, Pastore A, Tylzanowski P, Ny A, Lowe M, de Witte PA, Baelde HJ, van den Heuvel LP, Levtchenko E,


Elmonem MA, Khalil R, Khodaparast L, Khodaparast L, Arcolino FO, Morgan J, Pastore A, Tylzanowski P, Ny A, Lowe M, de Witte PA, Baelde HJ, van den Heuvel LP, Levtchenko E, (click to view)

Elmonem MA, Khalil R, Khodaparast L, Khodaparast L, Arcolino FO, Morgan J, Pastore A, Tylzanowski P, Ny A, Lowe M, de Witte PA, Baelde HJ, van den Heuvel LP, Levtchenko E,

Advertisement

Scientific reports 2017 02 157() 42583 doi 10.1038/srep42583
Abstract

The human ubiquitous protein cystinosin is responsible for transporting the disulphide amino acid cystine from the lysosomal compartment into the cytosol. In humans, Pathogenic mutations of CTNS lead to defective cystinosin function, intralysosomal cystine accumulation and the development of cystinosis. Kidneys are initially affected with generalized proximal tubular dysfunction (renal Fanconi syndrome), then the disease rapidly affects glomeruli and progresses towards end stage renal failure and multiple organ dysfunction. Animal models of cystinosis are limited, with only a Ctns knockout mouse reported, showing cystine accumulation and late signs of tubular dysfunction but lacking the glomerular phenotype. We established and characterized a mutant zebrafish model with a homozygous nonsense mutation (c.706 C > T; p.Q236X) in exon 8 of ctns. Cystinotic mutant larvae showed cystine accumulation, delayed development, and signs of pronephric glomerular and tubular dysfunction mimicking the early phenotype of human cystinotic patients. Furthermore, cystinotic larvae showed a significantly increased rate of apoptosis that could be ameliorated with cysteamine, the human cystine depleting therapy. Our data demonstrate that, ctns gene is essential for zebrafish pronephric podocyte and proximal tubular function and that the ctns-mutant can be used for studying the disease pathogenic mechanisms and for testing novel therapies for cystinosis.

Submit a Comment

Your email address will not be published. Required fields are marked *

nineteen − 13 =

[ HIDE/SHOW ]