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Defective INPP5E distribution In NPHP1-related Senior-Løken Syndrome
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  • Ke Ning,
  • Emilie Song,
  • Brent Sendayen,
  • Philipp Prosseda,
  • Kun-Che Chang,
  • Alireza Ghaffarieh,
  • Jorge Alvarado,
  • Biao Wang,
  • Nicolas Berbari,
  • Yang Hu,
  • Yang Sun
Ke Ning
Stanford University School of Medicine
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Emilie Song
Stanford University School of Medicine
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Brent Sendayen
Stanford University School of Medicine
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Philipp Prosseda
Stanford University School of Medicine
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Kun-Che Chang
Stanford University School of Medicine
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Alireza Ghaffarieh
Harvard Medical School Department of Medicine
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Jorge Alvarado
Stanford University School of Medicine
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Biao Wang
Stanford University School of Medicine
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Nicolas Berbari
Indiana University Purdue University at Indianapolis
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Yang Hu
Stanford University School of Medicine
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Yang Sun
Stanford University School of Medicine
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Abstract

Senior-Løken 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-Løken 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.