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Senior-Loken syndrome

MIM.266900

Friday 4 March 2005

Definition: The Senior-Loken syndrome is the autosomal recessive association of nephronophthisis with retinitis pigmentosa or retinal aplasia consistent with Leber amaurosis.

Synopsis

- ocular anomalies

  • retinitis pigmentosa
  • retinal aplasia/retinal hypoplasia
  • retinal dystrophy
  • retinal degeneration
  • tapetoretinal degeneration

- cerebrospinal anomalies

- skeletal anomalies

  • cone epiphyses
  • short stature
  • kyphoscoliosis
  • short metacarpals
  • cutis laxa

- congenital hepatic fibrosis

- renal anomalies

  • medullary cystic kidneys
    • nephronophthisis
    • vasopressin-resistant diabetes insipidus

Etiology

SLSN1 2q13 - NPHP1 MIM.256100
SLSN2
SLSN3 3q22 MIM.606995 NPHP3 MIM.604387
SLSN4 1p36 MIM.606966 NPHP4 MIM.607215
SLSN5 3q21.1 MIM.609254 IQCB1 (NPHP5)

Pathogenesis

- The renal-retinal syndrome Senior-Loken syndrome 1 (SLSN1), is caused by mutations in NPHP1-NPHP5. SLSN1 is characterized by the renal symptoms of NPHP and early-onset retinitis pigmentosa.

This phenotypic overlap can be explained by the fact that the primary cilium of renal epithelial cells is a structural equivalent to the connecting cilium of photoreceptor cells in the retina.

In the connecting cilia, cargo is trafficked along microtubule tracks from the photoreceptor inner segment to the outer segment through a motor protein complex that contains kinesin II, and back to the cell body through a cytoplasmic dynein. In this way, molecules of the visual pigment rhodopsin are transferred up and down the connecting cilia in every human retina each day.

An analogous intraciliary transport has been proposed for cilia of renal epithelial cells. Although nephrocystins might be part of the transported cargo, the exact composition of the cargo complex is unknown.

- The renal-retinal syndrome Senior-Loken syndrome 1 (SLSN1), which is caused by mutations in NPHP1-NPHP5, is characterized by the renal symptoms of NPHP and early-onset retinitis pigmentosa.

This phenotypic overlap can be explained by the fact that the primary cilium of renal epithelial cells is a structural equivalent to the connecting cilium of photoreceptor cells in the retina.

In the connecting cilia, cargo is trafficked along microtubule tracks from the photoreceptor inner segment to the outer segment through a motor protein complex that contains kinesin II, and back to the cell body through a cytoplasmic dynein.

In this way, 109 molecules of the visual pigment rhodopsin are transferred up and down the connecting cilia in every human retina each day. An analogous intraciliary transport has been proposed for cilia of renal epithelial cells. Although nephrocystins might be part of the transported cargo, the exact composition of the cargo complex is unknown.

See also

- Joubert syndrome

References

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

- von Schnakenburg C, Fliegauf M, Omran H. Nephrocystin and ciliary defects not only in the kidney? Pediatr Nephrol. 2007 Jun;22(6):765-9. PMID: 17310360

- Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O’Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005 Mar;37(3):282-8. PMID: 15723066

- Hildebrandt F, Otto E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet. 2005 Dec;6(12):928-40. PMID: 16341073