Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis

Abstract

Senior-Løken syndrome (SLS) is an autosomal recessive disease characterized by development of a retinitis pigmentosa (RP)- or Leber congenital amaurosis (LCA)-like retinal dystrophy and a medullary cystic kidney disease, nephronophthisis. Mutations in several genes (called nephrocystins) have been shown to cause SLS. The proteins encoded by these genes are localized in the connecting cilium of photoreceptor cells and in the primary cilium of kidney cells. Nephrocystins are thought to have a role in regulating transport of proteins bound to the outer segment/primary cilium; however, the precise molecular mechanisms are largely undetermined. This review will survey the biochemistry, cell biology and existing animal models for each of the nephrocystins as it relates to photoreceptor biology and pathogenesis of retinal degeneration.

Fig. 1

Fundus photograph of a patient diagnosed with Senior-Løken syndrome. Shown are classic findings in RP: bone-spicule shaped deposits, attenuation of blood vessels with macular sparing.

Figure 2

Motif and domain structure of NPHP proteins. The nephrocystins contain the following predicted motifs: NPHP1, coiled-coil (CD), SRC Homology 3 (SH3) and a nephrocystin homology domain (NHD) (Otto et al., 2000b). INVS/NPHP2, ANK, N-terminal Ankyrin repeat, ICP4, transcriptional regulator domain, flanked by CD and IQ calmodulin-binding motifs (IQ) (Otto et al., 2003; Lienkamp et al., 2012). NPHP3, myr, N-terminal myristoylation signal; CD; TTL, tubulin-tyrosine ligase domain; TPR, tetratricopeptide repeat domains (Olbrich et al., 2003; Wright et al., 2011). NPHP4, PR, proline-rich region (Mollet et al., 2002). NPHP5, a CD domain flanked by 2 IQ calmodulin binding motifs (Otto et al., 2005). NPHP6, multiple CDs throughout the molecule; myo tail, myosin tail homology domain (Chang et al., 2006). NPHP7, several Zinc finger motifs (Zhang et al., 2002). NPHP8, S_TKc, N-terminal serine/threonine protein kinase catalytic domain; RCC1, C-terminal Regulator of chromosome condensation 1 domain (Zalli et al., 2012). NPHP10, NGD, N-terminal globular domain; eight CDs (Otto et al., 2010). NPHP11, TM, transmembrane domains (Otto et al., 2009). NPHP12, TPR, tetratricopeptide domains (Davis et al., 2011). NPHP13, WDR, WD repeats (Lin et al., 2003).