This cartoon summarizes a new unifying pathogenic theory of cystic kidney disease, as derived from gene identification of inversin/NPHP2 (Olbrich, H., et al. 2003. Nature Genetics 34:455–459; Watnick, T., and Germino, G. 2003. Nature Genetics 34:355–356). This theory states that virtually all proteins (cystoproteins) mutated in cystic kidney disease of humans, mice, or zebrafish show expression of their encoded proteins in primary cilia, basal bodies, or centrosomes. The horizontal axis symbolizes the flow of genetic information from genes over proteins to disease phenotypes. The vertical axis represents evolutionary time.

a: On the evolutionary scale, genes responsible for renal cystic disease in vertebrates have been conserved for more than 1.5 billion years of evolution, including in the flagella of the unicellular organism Chlamydomonas reinhardtii.

b: Many orthologs of human cystic kidney disease genes are expressed in ciliated neurons in the head and tail of the nematode Caenorhabditis elegans, where they lead to a male mating phenotype if knocked down (e.g., lov-1 or nph-4; see e). Bardet-Biedl syndrome (BBS) exhibits an NPHP-like kidney phenotype. NPHP4 and most proteins mutated in BBS are conserved as basal body components of motile cilia (flagella) in Ch. reinhardtii, where mutations in these genes lead to a phenotype of defective intraflagellar transport or propulsion (see e).

c: Many cystoproteins directly interact with each other (e.g., NPHP1 and NPHP2/inversin).

d: All genes mutated in cystic kidney diseases of humans, mice, or zebrafish show expression of their encoded proteins in primary cilia, basal bodies, or centrosomes. This places primary cilia and centrosomes at the center of these disease processes. (Column d has no vertical dimension.)

e–g: The convergence of the pathogenesis of cystic kidney diseases at sensory cilia that serve distinct functions in different tissues may explain the broad organ involvement (pleiotropy) of NPHP and BBS; i.e., many different organ systems are affected through defects of sensory cilia and ciliated neurons. Pleiotropic phenotypes in NPHP or BBS include cystic kidney disease, retinitis pigmentosa, infertility, diabetes mellitus, and other diseases of premature aging of organs.

Adapted from Hildebrandt, F., and Otto, E. 2005. Nature Reviews Genetics 6:928–940.