nephronophthisis complex

Types

 juvenile nephronophtisis
 Joubert syndrome
 Senior-Loken syndrome
 Arima syndrome
 COACH syndrome

Pathogenesis

Nephronophthisis (NPHPs), an autosomal recessive cystic kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life.

Contrary to polycystic kidney disease, NPHPs shows normal or diminished kidney size, cysts are concentrated at the corticomedullary junction, and tubulointerstitial fibrosis is dominant.

NPHPs can be associated with retinitis pigmentosa (Senior-Loken syndrome), liver fibrosis, and cerebellar vermis aplasia (Joubert syndrome) in approximately 10% of patients.

The concept of "Ciliopathies" has helped advance a new unifying theory of cystic kidney diseases. This theory states that the products of all genes that are mutated in cystic kidney diseases in humans, mice, or zebrafish are expressed in primary cilia or centrosomes of renal epithelial cells.

Primary cilia are sensory organelles that connect mechanosensory, visual, osmotic, and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity.

The ciliary theory explains the multiple organ involvement in NPHP regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation.

Mutations in NPHPs genes (NPHP1, NPHP2, NPHP3, NPHP4, NPHP5) cause defects in signaling mechanisms, including the noncanonical Wnt signaling pathway.

The "ciliopathy" NPHP thereby is caused by defects in tissue differentiation and maintenance as a result of impaired processing of extracellular cues. Nephrocystins, the proteins that are encoded by NPHP genes, are highly conserved in evolution.

See also

 Joubert syndrome (germline NPHP1 mutations)

References

 Hildebrandt F, Zhou W. Nephronophthisis-Associated Ciliopathies.
J Am Soc Nephrol. 2007 May 18; PMID: 17513324