Many Genes-One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders

Abstract

Nephronophthisis (NPHP) is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required.

Keywords: DNA damage; Joubert syndrome; centrosome; cilia; ciliopathy; cyclic adenosine monophosphate; molecular genetics; nephronophthisis.

Figure 1

Typical histological features of nephronophthisis. (A) Light microscopy image. PAS stain demonstrates a globally sclerosed glomerulus and some periglomerular fibrosis. There is moderate interstitial fibrosis with chronic inflammation and thickening of tubular basement membranes. (B) Light microscopy image. H&E stain shows tubular atrophy with hyaline casts, moderate interstitial fibrosis, and patchy mononuclear inflammation. (C) Electron microscopy image. Tubular basement membrane demonstrates thickening and multilayering. Scale bar 2 µm.