Autosomal Recessive Retinitis Pigmentosa 26 (RP26) via the CERKL Gene

Retinitis pigmentosa (RP; OMIM # 268000) or rod cone dystrophies (RCDs) represent a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42 (11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia ("night blindness"), followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-334, 1999). RP26 (OMIM # 608380) is characterized by equally affected cone and rod systems and pronounced macular atrophy (Avila-Fernandez et al. Invest Ophthalmol Vis Sci 49(6):2709-2713, 2008).

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (ad), autosomal recessive (ar) or X-linked (XL) inheritance. To date, over 50 loci have been linked to nonsyndromic RP and 18, 27 and 2 genes have been identified that are involved with adRP, arRP, and XLRP, respectively (RetNet). Ceramide kinase like protein, which is encoded by CERKL, is homologous to the Ceramide kinase protein (CERK: 29% identity; 50% similarity) (Sugiura et al. J Biol Chem 277(26):23294-23300, 2002), but does not have the same function as CERK (Bornancin et al. Biochim Biophys Acta 1687(1-3):31-43, 2005). In situ hybridization analysis on adult murine retina sections revealed that the CERKL protein is predominantly synthesized in the retinal ganglion cell layer and to a lesser extent in the inner nuclear and photoreceptor cell layers (Tuson et al. Am J Hum Genet 74(1):128-138, 2004). Ceramides are metabolites of the structural membrane component sphingolipid and have been implicated in apoptosis, growth suppression, and the stress response (Hannun et al. Science 274(5294):1855-1859, 1996). Tuson et al. (2004), linked RP to ceramide-induced apoptosis and suggested that the ceramide kinases convert ceramide into ceramide-1-phosphate and act as antiapoptotic and neuroprotective agents (Tuson et al., 2004). Kinase activity of CERKL is not yet proven (Bornancin et al., 2005). It has also been reported that CERKL contributes to nucleolar localization. Missense mutations in CERKL prevent the active transport of CERKL from the cytoplasm to the nucleolus. This would lead to the accumulation of CERKL in the cytoplasm that might induce apoptotic cell death and ultimately retinal degeneration (Ali et al. Mol Vis 14:1960-1964, 2008; Aleman et al. Invest Ophthalmol Vis Sci 50(12):5944-5954, 2009). So far, about 10 mutations (missense, nonsense, splicing, small insertions and deletions) have been associated with arRP26 (The Human Gene Mutation Database).

CERKL mutation screening in two hundred and ten unrelated Spanish families with nonsyndromic arRP identified a homozygous nonsense mutation (p.Arg257*) in all seven affected families (~3.3%) (Avila-Fernandez et al. Invest Ophthalmol Vis Sci 49(6):2709-2713, 2008). Another mutation analysis identified CERKL mutations in 2% of CRD cases (2/123), which were not present in 200 ethnically matched control alleles (Littink et al. Invest Ophthalmol Vis Sci 51(11):5943-5951, 2010). Another study identified CERKL mutations in two out of sixteen RP patients (~12.5%), which were not present in the control cohorts of 95 healthy North American or 95 Japanese individuals. All these mutations cosegregated with RP as recessive, pathogenic alleles in all family members (Nishiguchi et al Proc Natl Acad Sci USA 2013 Sep 16, Epub ahead of print). A prevalent CERKL founder mutation (c.238+1G>A) has been identified that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population (Auslender et al. Invest Ophthalmol Vis Sci 48(12):5431-5438, 2007).

So far, no gross deletions or duplications have been reported in CERKL (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CERKL gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.