The ciliopathies: a transitional model into systems biology of human genetic disease

Abstract

The last decade has witnessed an explosion in the identification of genes, mutations in which appear sufficient to cause clinical phenotypes in humans. This is especially true for disorders of ciliary dysfunction in which an excess of 50 causal loci are now known; this discovery was driven partly by an improved understanding of the protein composition of the cilium and the co-occurrence of clinical phenotypes associated with ciliary dysfunction. Despite this progress, the fundamental challenge of predicting phenotype and or clinical progression based on single locus information remains unsolved. Here, we explore how the combinatorial knowledge of allele quality and quantity, an improved understanding of the biological composition of the primary cilium, and the expanded appreciation of the subcellular roles of this organelle can be synthesized to generate improved models that can explain both causality but also variable penetrance and expressivity.

Figure 1

Schematic representation of functional ciliary complexes and their components. Four biochemically characterized ciliary complexes have emerged as facilitators of discrete functions in the cilium. First, the BBSome (purple) consists of seven proteins, mutations in which have been implicated in Bardet-Biedl syndrome. The BBSome has been proposed to interact with BBS3/ARL6 at the plasma membrane and sort membrane proteins to the cilium [43,120]. Second, the transition zone complex (orange) has emerged as a regulator of ciliogenesis and ciliary membrane assembly and is comprised of proteins encoded by MKS and JBTS genes [36,39,121,122]. Third, once loaded into the primary cilium, anterograde protein transport is conducted with IFT complex B proteins and heterotrimeric kinesin motors (green) [44]. Finally, retrograde recycling of proteins from the tip of the cilium back to the cell body is governed by IFT complex A proteins and dynein motors (blue) [44], all of which have been implicated in the skeletal dysplasia ciliopathies including Sensenbrenner syndrome, JATD, and SRP.