Modeling human disease in humans: the ciliopathies

Abstract

Soon, the genetic basis of most human Mendelian diseases will be solved. The next challenge will be to leverage this information to uncover basic mechanisms of disease and develop new therapies. To understand how this transformation is already beginning to unfold, we focus on the ciliopathies, a class of multi-organ diseases caused by disruption of the primary cilium. Through a convergence of data involving mutant gene discovery, proteomics, and cell biology, more than a dozen phenotypically distinguishable conditions are now united as ciliopathies. Sitting at the interface between simple and complex genetic conditions, these diseases provide clues to the future direction of human genetics.

Figure 1. Human genetic interactions in the ciliopathy spectrum

Diseased individuals are in color, with severity represented by darker shading. Phenocopies refers to the finding that patients with homozygous or compound heterozygous mutations in two different genes (i.e. AHI1 or INPP5E) can show indistinguishable JBTS phenotypes. Multiple allelism at the same locus indicates that mutations in a single gene (i.e. CEP290) can lead to various distinguishable phenotypes. Modifiers refers to evidence that potentially deleterious sequence changes in a gene like AHI1 can modify in quantifiable ways the phenotype observed in patients with NPHP1 mutations. Black: normal chromosome; Red: mutant chromosome. AHI1: abelson helper integration site 1; INPP5E: inositol polyphosphate-5-phosphatase E; CEP290: centrosomal protein 290kDa; NPHP1: nephrocystin 1. BBS: Bardet-Biedl syndrome; JBTS: Joubert syndrome; LCA: Leber congenital amaurosis; MKS: Meckel syndrome; NPHP: nephronophthisis; RD: retinal dystrophy; SLS: Senior Loken syndrome.

Figure 2. Phenotypic and interactome diversity of the ciliopathies based upon major organ involvement

A. Disease is represented below by abbreviation, and involvement of major organ listed above. B. Major ciliopathy diseases (color coded by severity), and gene mutated in each condition (red) linked by black bar with more common causes showing thicker lines. C. The same gene map, now indicating evidence for direct interaction between protein products. Protein interaction networks identified from published data demonstrating major clustering of interactions corresponding to disease networks. Note that genes causing a particular disorder tend to have products that interact, although there are many genes without known connections. Note that some genes like CEP290, which can cause several different diseases, should serve as hubs, but have few demonstrated physical interactions to date. BBS: Bardet-Biedl syndrome; JBTS: Joubert syndrome; LCA: Leber congenital amaurosis; MKS: Meckel syndrome; NPHP: nephronophthisis; OFD: Orofaciodigital syndrome; SLS: Senior Loken syndrome.

Figure 3. Discovery pipeline for mechanism of disease: past and future paradigms

A. Former strategy to identify disease mechanisms, starting with ascertainment of pedigrees for linkage, disease mapping to a particular chromosomal locus, and candidate gene Sanger sequencing. Once a mutant gene was identified, animal models were created to understand the mechanism. B. The future paradigm bypasses the need for informative pedigrees and disease mapping, instead going directly from patient ascertainment to genome sequencing, then to variant identification and expanded to identification of modifiers and mutational load. In parallel, patient-specific disease modeling using human cells coupled with protein interaction networks and therapeutic drug screening can further uncover disease mechanisms and help develop better treatments.