Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome

Abstract

Objective: To investigate whether mutations in NPHP5 can cause Leber congenital amaurosis (LCA) without early-onset renal disease.

Methods: DNA samples from 276 individuals with nonsyndromic LCA were screened for variations in the NPHP5 gene. Each had been previously screened for mutations in 8 known LCA genes without identifying a disease-causing genotype.

Results: Nine of the 276 LCA probands (3.2%) harbored 2 plausible disease-causing mutations (7 different alleles) in NPHP5. Four of these have been previously reported in patients with Senior-Loken syndrome (F141del, R461X, H506del, and R489X) and 3 are novel (A111del, E346X, and R455X). All 9 patients had severe visual loss from early childhood but none had overt renal disease in the first decade of life. Two patients were diagnosed with nephronophthisis in the second decade. Retinal imaging studies showed retained photoreceptor nuclei and retinal pigment epithelium integrity mainly in the cone-rich central retina, a phenotype with strong similarities to that of NPHP6 disease.

Conclusions: Mutations in NPHP5 can cause LCA without early-onset renal disease. Abnormalities observed in the photoreceptor outer segments (a cilial structure) may explain the severe visual loss in NPHP5 -associated LCA. Clinical Relevance The persistence of central photoreceptor nuclei despite severe visual loss in NPHP5 disease is encouraging for future therapeutic interventions.

Figure 1

Chromosome 3 genotyping of patient P3 and his family. These individuals were genotyped at 11 loci distributed across chromosome 3. The mutation (H506del) lies at 121.49 centimorgans (cM) (asterisk). For all 11 markers, the patient is homozygous for a maternal marker allele, consistent with maternal uniparental isodisomy.

Figure 2

NPHP5-mutant retinas analyzed for photoreceptor and retinal pigment epithelium disease. A, Cross-sectional images along the vertical meridian are shown in a normal subject (left panel) and 3 patients with NPHP5 mutation of different ages (right 3 panels). The photoreceptor nuclear layer is highlighted (blue); inner and outer segment laminae and cilial structure are indicated (bracketed with the photoreceptor nuclear layer in the normal subject and unlabeled black arrows in patients). B, Topography of photoreceptor layer thickness in a normal retina (left) and 2 NPHP5-mutant retinas (right panels), displayed in pseudocolor. The location of the optic nerve head and major retinal blood vessels are overlaid (black or white) for reference. The fovea and optic nerve head are labeled in the normal subject. C, Retinal pigment epithelium integrity as measured with near infrared autofluorescence in a representative normal subject (left panel) and in the patients with NPHP5 mutation. Higher intensity represents greater melanin content. F indicates fovea; S, superior; T, temporal.