Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa

Abstract

Purpose: The purpose of this project was to determine the spectrum and frequency of mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) that cause autosomal dominant retinitis pigmentosa (adRP).

Methods: A well-characterized adRP cohort of 251 families was tested for mutations in the exons and intron/exon junctions of SNRNP200 using fluorescent dideoxy sequencing. An additional 21 adRP families from the eyeGENE® Network were tested for possible mutations. Bioinformatic and segregation analysis was performed on novel variants.

Results: SNRNP200 mutations were identified in seven of the families tested. Two previously reported mutations, p.Arg681Cys and p.Ser1087Leu, were found in two families each. One family had the previously reported p.Arg681His mutation. Two novel SNRNP200 variants, p.Pro682Ser and p.Ala542Val, were also identified in one family each. Bioinformatic and segregation analyses suggested that these novel variants are likely to be pathogenic. Clinical examination of patients with SNRNP200 mutations showed a wide range of clinical symptoms and severity, including one instance of non-penetrance.

Conclusions: Mutations in SNRNP200 caused 1.6% of disease in our adRP cohort. Pathogenic mutations were found primarily in exons 16 and 25, but the novel p.Ala542Val mutation in exon 13 suggests that variation in other genetic regions is also responsible for causing dominant disease. SNRNP200 mutations were associated with a wide range of clinical symptoms similar to those of individuals with other splice-factor gene mutations.

Figure 1

Families with SNRNP200 mutations. A: Two families with a c.2041C>T, p.Arg681His mutation. B: Two families with a c.3260C>T, p.Ser1087Leu mutation C: Family with a c.2042G>A, p.Arg681His mutation D: Family with c.1625C>T, p.Ala542Val mutation E: Family with a c.2044C>T, p.Pro682Ser mutation. Circles indicate women; squares indicate men. Black filled symbols are affected individuals, grey filled symbols are possibly affected individuals, and open symbols are unaffected individuals. Arrows indicated each family’s proband. Individual ID numbers corresponding to Table 2 are underneath each symbol.

Figure 2

Clinical features in UTAD701–01, right eye. A: Color fundus photograph shows retinal vascular attenuation and mild disc pallor; thin white lines outline the retinal region imaged using adaptive optics scanning laser ophthalmoscopy (AOSLO); the thick horizontal white line indicates the spectral domain optical coherence tomography (SD-OCT) location. B: Goldmann visual field testing shows constriction to the I4e target (blue lines). C: Horizontal SD-OCT through the anatomic fovea shows cystoid macular edema near the fovea; the inner segment ellipsoid zone band extends about 5 degrees from the fovea with loss of outer retinal layers at greater eccentricities. D: High-resolution foveal images acquired using adaptive optics scanning laser ophthalmoscopy (AOSLO) reveal walls of cystoid spaces (dark lines). Cones are visible within the cystoid spaces. E: Cone spacing increased by 3.5–7.9 standard deviations above the normal mean (white numbers: standard deviations from normal mean, small white spots and the red circle indicate fixation locus). Scale bars=1°.

Figure 3

Fundus photographs from individuals with small nuclear riboprotein 200 kDa mutations. A: UTAD565-02 at age 59 with moderatively advanced retinitis pigmentosa . Her right eye fundus shows diffuse atrophy of the optic nerve and the retina outside the macula with heavy pigmentary deposits in the equator and vascular attenuation, while the macula area shows intact retinal pigment epithelium with no foveal reflex. B: RFS048–4884 at age 40 showed severe vascular attenuation and disc pallor. Extensive pigmentary disturbances were seen throughout the peripheral retina. C: RFS048-5420 at age 14 showed moderate vascular attenuation and disc pallor. Moderate pigment clumping was seen in the periphery. D: UTAD701-01 at age 34 shows vascular attenuation, mild disc pallor, and heterogeneous, mottled fundus pigment along the temporal arcades with preserved pigmentation in the central macula.