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.
Highlights
Nephronophthisis (NPHP) is an autosomal recessive inherited kidney disease, which leads to endstage renal disease (ESRD) typically within the first three decades of life [1]
We will review the clinical and histological features of the disease and its conventional classification before reviewing the underlying genetic causes and the ciliopathy syndromes associated with NPHP
ANKS6 localizes to the inversin compartment and links the NPHP proteins NPHP2, NPHP3, and NPHP9 to NEK8
Summary
Nephronophthisis (NPHP) is an autosomal recessive inherited kidney disease, which leads to endstage renal disease (ESRD) typically within the first three decades of life [1]. ANKS6 localizes to the inversin compartment and links the NPHP proteins NPHP2, NPHP3, and NPHP9 to NEK8 This functional role of ANKS6 in an NPHP module may explain the phenotypic overlap that includes abnormalities in heart and liver, seen in the patients carrying individual mutations in these genes [65, 66]. Defects in primary cilia associated with cystic kidney disease were initially noted in Ift mutant mice [120] This link between NPHP and cilia was confirmed in human disease established after the discovery that INVS mutations cause infantile NPHP and that the encoded protein inversin interacts with nephrocystin-1 and β-tubulin, colocalizing with them to the primary cilia of renal tubular cells [11]. More recent studies have challenged this hypothesis [122, 123]
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