Defective INPP5E distribution In NPHP1-related Senior-Løken Syndrome

Senior-Loken syndrome is a rare genetic disorder which presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness. The most frequent cause of juvenile nephronophthisis is mutation in the nephronophthisis type 1 (NPHP1) gene. NPHP1 encodes the protein nephrocystin-1, which functions at the transition zone (TZ) of primary cilia. Here we report a 9-year-old Senior-Loken syndrome patient with NPHP1 deletion, who presents with a decreased electroretinogram consistent with early retinal degeneration. The patient had undergone bilateral nephrectomy and a renal transplant. Immunohistochemistry and electron microscopy of the resected kidney showed disorganized cystic structures with loss of cilia in renal tubules. Phosphoinositides have been recently recognized as critical components of the ciliary membrane and immunostaining of kidney sections for phosphoinositide 5-phosphatases (INPP5E) showed loss of staining compared to a healthy control. The decreased expression of INPP5E specifically in the primary cilium, coupled with disorganized cilia morphology, suggests a novel role of NPHP1 that it is involved in regulating ciliary phosphoinositide in the ciliary membrane of renal tubular cells.