Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Scientific Background

NPHP is an autosomal recessive cystic kidney disease, which is thought to cause 6-10% of all cases of terminal kidney failure in children and is therefore the cause of approx. 10% of all kidney transplantations in children. In addition, extra-renal manifestations such as retinitis pigmentosa (Senior–Løken syndrome), cogan-type oculomotor apraxia (Cogan syndrome) as well as optic nerve coloboma and cerebellar vermis aplasia (Joubert syndrome) are seen. Frequency for NPHP is approx. 1 in 100,000.

NPHP always affects both kidneys. In normal-sized or slightly smaller-sized kidneys, macroscopic examinations show a fine, superficial granulation. In the region of the corticomedullary junction, 5 to 50 cysts may develop, which may reach a diameter ranging from 5 to 15 mm. In the early stage of NPHP, light microscopy shows characteristic changes such as significant tubular basement membrane thickening as well as a lymphohistiocytic, peritubular infiltration which later lead to a diffuse sclerosing tubulointerstitial nephropathy. Electron microscopy shows thickening, fragmentation and folding with deposition of fibroblasts.

NPHP belongs to the group of ciliopathies. Cilia are specific cell protuberances with various tasks. They serve, for example, as mechano, osmotic and chemo sensors. Moreover, they play a major role in numerous signaling pathways and are crucial for appropriate organ development, maintaining tissue homeostasis and fundamental developmental processes.

NPHP shows significant gene locus heterogeneity. So far, mutations in 15 genes have been associated with NPHP. The gene products are termed nephrocystins: NPHP1 to NPHP13, AHI1, and CC2D2A. In approx. 85% of all patients suffering from NPHP, a homozygous deletion of the NPHP1 gene can be detected.