PhD ThesisCystic kidney diseases are a fascinating cluster of discrete conditions and an important,
common cause of established renal failure. Both isolated and syndromic inherited
cystic kidney diseases are known to be linked by their pathogenesis involving ciliary
dysfunction. Interestingly to date, all mutated genes which have been related to cystic
kidney disease, encode proteins which are located on cilia, the basal body or
centrosomes and are required for ciliary function. To date, over 50 causal genes have
been identified and are capable of causing additional disease phenotypes, such as
neurological disorders and blindness, often of variable severity. Understanding this
clinical heterogeneity may considerably guide appropriate genetic counselling and
screening of patients for relevant complications.
Zebrafish are a well-recognised animal model, their advantages of: transparency;
conserved genome; representative kidney and rapid external development; make them
useful for studying organogenesis in the context of disease. Furthermore the ability to
perform combined gene knockdown in zebrafish, to study the effect of oliogenicity,
which was proposed to influence clinical phenotypes in cystic kidney disease related
ciliopathies, was of interest.
Using zebrafish models, this work studied the impact of four key genes, independently
and in combination: ahi1, cc2d2a, nphp6 and mks3 on the development of cystic kidney
disease and ciliopathy phenotypes, to resemble the human diseases nephronophthisis
(NPHP), Joubert syndrome (JBTS) and Meckel Gruber syndrome, (MKS). A frequent
finding in zebrafish morphants was a reduction in the number of cilia, which was
usually associated with abnormal development of left-right body patterning and cystic
kidney disease. Additionally, combined gene knockdown of: nphp6 and cc2d2a; ahi1
and cc2d2a; ahi1 and nphp6 was associated with a synergistic increase in disease
phenotypes, suggesting an interaction between these genes.
In conclusion, zebrafish are a powerful developmental model to study and ideally
improve understanding of cystic kidney disease related ciliopathies.Mason Medical Research Group, Medical Research Council and Kidney Research UK