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Exploring the genetics of nephronophthisis and Joubert Syndrome…more than monogenic cystic renal diseases?!


Understanding the pathogenesis of the autosomal recessive cystic kidney disease, nephronophthisis (NPHP) remains a challenge. NPHP is associated with extra-renal disease in 10-15%, including abnormal eye and cerebellar development, this combination of problems is called Joubert Syndrome, JS. NPHP and JS are ciliopathies because the encoded proteins of all mutated genes are found in primary cilia/associated architecture. NPHP and JS are genetically heterogenous, with mutations in a single gene such as NPHP6, AHI1 or CC2D2A being sufficient to cause disease. Although homozygous mutations are identified in most cases, some patients have an additional heterozygous mutation in another gene, leading to hypotheses of epistasis modifying the clinical phenotype.


We aim to use zebrafish, in whom nphp6, ahi1 and cc2d2a are highly conserved, as a model organism, to evaluate potential genetic interactions and the influence this may have on the development of NPHP and JS.


Splice blocking antisense morpholino oligonucleotides (MOs) directed towards nphp6, ahi1 and cc2d2a were injected individually, and in combination, into 1-4 cell stage wild type zebrafish embryos. Embryos were phenotyped using light microscopy at 72 hours post fertilisation (hpf).


Each MO individually induces a morphant phenotype including curly tail, cardiac oedema, hydrocephalus, pronephric cysts, abnormal eye and ear development. Co-injection of low dose ahi1 and nphp6 MOs or ahi1 and cc2d2a MOs leads to synergy of the morphant phenotypes.


The synergistic increase in the morphant phenotype following combined knockdown of ahi1 and nphp6 or ahi1 and cc2d2a in zebrafish implicates a genetic interaction.

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Correspondence to RJ Simms.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Simms, R., Hynes, M. & Sayer, J. Exploring the genetics of nephronophthisis and Joubert Syndrome…more than monogenic cystic renal diseases?!. Cilia 1 (Suppl 1), P103 (2012).

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  • Zebrafish Embryo
  • Morpholino
  • Cystic Kidney
  • Morpholino Oligonucleotide
  • Joubert Syndrome