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Childhood Genetic Kidney Diseases: Delineating Etiology, Pathomechanisms, and Novel Therapies

Research Summary

Friedhelm Hildebrandt is identifying and characterizing genes responsible for childhood kidney diseases, enlisting the aid of thousands of patients worldwide.

Chronic kidney diseases (CKDs) take one of the highest tolls on human health. They insidiously lead to terminal kidney failure, with the affected individual requiring dialysis or kidney transplantation for survival. More than 20 million individuals in the United States alone suffer from CKD. In children, CKD severely interferes with growth, development, schooling, and social development. Identification of monogenic disease genes for CKD has surfaced as a strong paradigm for unraveling disease mechanisms: it reveals the primary cause of a disease, allows for unequivocal molecular genetic diagnostics, permits the generation of genetic animal models, and facilitates the development of new forms of treatment.

Through interaction with patients worldwide, my laboratory has elucidated disease mechanisms for three disease groups: cystic/fibrotic kidney diseases, nephrotic syndrome, and congenital abnormalities of the kidney and urinary tract (CAKUT). These disorders, the most frequent causes of kidney failure in children, are also associated with visual and auditory defects. Our findings, together with the work of others, led to a new unifying pathogenic theory that defines cystic kidney diseases as ciliopathies (Figure 1). Animal models that we generate for these disease genes allow high-throughput testing of new drugs. My laboratory, which has examined more than 5,000 families, offers worldwide mutation analysis of these genes on an experimental basis (www.renalgenes.org). Our findings create a foundation for developing evidence-based treatment guidelines for these disorders.

Figure 1: Evolutionary conservation of ciliopathy genes and organ involvement...

My lab was involved in the discovery and definition of ciliopathies, genetic defects in functional components of primary cilia. Primary cilia are sensory organelles produced by virtually all vertebrate cell types. They are structurally and functionally highly conserved in evolution. Cilia represent a ubiquitous system for sensing cell-external signals, including olfactory and hormonal sensation and photo-, mechano-, and thermosensation. The structure of primary cilia is related to the structure of motile cilia or flagella (Figure 1). The connection of primary cilia to basal bodies, from which they are assembled, and to their equivalent centrosome implicates them in mechanisms of cell cycle regulation. Ciliopathies cause premature failure of multiple organ systems. In particular, nephronophthisis (NPHP) is a recessive cystic kidney disease that inescapably leads to terminal kidney failure and is its most frequent genetic cause in children and young adults. NPHP can be associated with blindness (retinal degeneration), liver fibrosis, mental retardation, and bone malformations. In Bardet-Biedl syndrome, NPHP is also associated with infertility, diabetes mellitus, and obesity. No specific treatment is available for any of the ciliopathies.

A Unifying Theory of Cystic Kidney Disease
My lab has used homozygosity mapping and whole exome resequencing to identify causes of the ciliopathy NPHP. Specifically, we identified mutations in 15 different genes (NPHP1–15) as causing NPHP with retinal degeneration. This led to the discovery of new gene products that are expressed in primary cilia and defined new functions and signaling mechanisms of cilia and centrosomes. Our identification of mutations in theinversin/NPHP2 gene as causes of NPHP type 2 contributed to a new unifying theory of cystic kidney disease. This theory states that all genes that, if mutated, cause kidney cysts in humans, mice, or zebrafish express their encoded proteins in primary cilia or centrosomes (see Figure).

On the basis of our discovery of mutations in the geneNPHP3 as a new cause of NPHP in humans and as the cause of the renal polycystic disease pcy in mice, another group devised the first efficient treatment of the disease in the pcy mouse model. With discovery of the NPHP4and NPHP5 genes and their expression in primary cilia, we were able to explain the eye involvement in NPHP, since cilia are an important structural component of photoreceptors. Furthermore, our identification of mutations in NPHP6/CEP290 as the cause of NPHP associated with blindness, ataxia, and mental retardation implicated the planar cell polarity signaling pathway in the pathogenesis of NPHP and established phenotypic conservation in the model organisms Ciona intestinalis (sea squirt) and zebrafish. This finding will allow for high-throughput testing of drugs that may ameliorate the disease course of ciliopathies. In addition, our identification of mutations in GLIS2 as the cause of NPHP type 7 demonstrated involvement of sonic hedgehog signaling in the pathogenesis of ciliopathies.

The Pathogenesis of Ciliopathies
Recently, it was realized that many pediatric kidney diseases that had not been considered genetic in origin can be caused in a child by recessive mutations in only a single gene out of the 25,000 genes encoded by the human genome. In ciliopathies, although a mutation in a single recessive gene is sufficient to cause the disease in a certain patient, hundreds of different genes are responsible for similar ciliopathies in different patients. Identification of these genes provides the opportunity to define most components of the pathogenic pathways of ciliopathies that are necessary for ciliary function, based on the finding that a mutation in each of these genes is individually sufficient to cause a ciliopathy.

In the past 15 years my lab has ascertained DNA samples from more than 1,500 different families worldwide with NPHP-like ciliopathies with variable organ involvement. Our data from a total genome search for linkage in 75 consanguineous kindred with NPHP demonstrate that at least 50 further unknown causative genes exist for NPHP-like ciliopathies. We apply the powerful approach of homozygosity mapping and whole exome resequencing to identify the functional components of primary cilia, to refine the unifying pathogenic theory for ciliopathies, and to develop high-throughput drug testing in suitable animal models. This approach will allow us to unravel the signaling networks involved in ciliopathies, thereby advancing a unifying theory of renal cystic disease, retinal degeneration, and other ciliopathies. Recently, we discovered a surprising link of DNA damage response signaling to ciliopathies.

Nephrotic Syndrome
My laboratory also works on the genetics and pathophysiology of nephrotic syndrome (NS), in which loss of protein in the urine leads to body swelling and kidney failure. A treatment-resistant form of NS, focal segmental glomerulosclerosis (FSGS), invariably leads to terminal kidney failure and may even destroy a kidney transplant. The disease mechanisms remain unknown, and there is no treatment for FSGS. We have been offering mutation analysis worldwide of genes known to cause NS and have examined more than 1,200 samples so far. Surprisingly, ~25 percent of all cases of treatment-resistant NS are caused by mutations in a single gene (podocin), and 66 percent of occurrences in the first year of life are caused by mutations in only four different genes. We also found that patients with NPHS2mutations do not respond to steroid treatment, which has consequences for the clinical management of FSGS. These studies will provide useful biomarkers for clinical applications, such as a disease classification based on genetic origin of future therapeutic trials.

By positional cloning, we have identified PLCE1 as the first gene mutated in an NS variant that responds to treatment. By plce1 knockdown in zebrafish, we recapitulated the symptoms of NS in humans. This zebrafish model of human NS allows us to study disease mechanisms and develop new forms of treatment for NS. We continue to perform gene identification in NS by homozygosity mapping in worldwide cohorts of children with NS (www.renalgenes.org). Recently, whole exome resequencing allowed us to identify 10 novel genes as mutated in NS, revealing an ability to treat two of these variants. We are currently recapitulating human NS syndrome in zebrafish models using the TALEN (transcription activator-like effector nuclease) approach, which will permit screening for small molecules that may mitigate NS.

Congenital Anomalies of the Kidney and Urinary Tract
Congenital anomalies of the kidney and urinary tract malformations (CAKUT) are by far the most frequent cause of terminal renal failure in children and adolescents (50 percent). My lab has identified, by positional cloning, mutations in SIX1 as causing branchio-oto-renal syndrome (BOR). For these mutations we demonstrated defects in EYA1-SIX1 protein-protein interaction and SIX1-DNA interaction. We are now using positional cloning and protein-protein interaction studies to identify additional members of the EYA1-SIX transcriptional complex as functional candidate genes that may be mutated in BOR. This work recently led to the identification of mutations in SIX5 as a new cause for BOR. Recently, by whole exome resequencing, we found a mutation of TRAP1 to be an additional cause of CAKUT.

These studies will help elucidate the pathogenesis of urinary tract malformations and will open inroads into possible preventive measures.

The work is also supported by the National Institutes of Health, the Doris Duke Charitable Foundation, the Thrasher Research Fund, and the March of Dimes Foundation.

As of October 15, 2012

Scientist Profile

Boston Children's Hospital
Cell Biology, Genetics