MERTK missense variants in three patients with retinitis pigmentosa

Abstract

Background: MERTK (MER proto-oncogene, tyrosine kinase) is a transmembrane protein essential in regulating photoreceptor outer segment phagocytosis. Biallelic mutations in MERTK cause retinal degeneration. Here we present the retinal phenotype of three patients with missense variants in MERTK.

Materials and methods: All patients underwent a full clinical examination, fundus photography, short-wavelength fundus autofluorescence and optical coherence tomography imaging. Two patients also underwent Goldmann visual field testing and electroretinography was undertaken for the third patient. Molecular genetic testing was undertaken using next generation or whole-exome sequencing with all variants confirmed by Sanger sequencing.

Results: The first patient was a 29-year-old female heterozygous for a missense variant (c.1133C>T, p.Thr378 Met) and a nonsense variant (c.1744_1751delinsT, p.Ile582Ter) in MERTK. The second patient was a 26-year-old male homozygous for a c.2163T>A, p.His721Gln variant in MERTK. The third patient was an 11-year-old female heterozygous for a deletion of exons 5-19 and a missense variant (c.1866 G>C, p.Lys622Asn) in MERTK. Reduced night vision was the initial symptom in all patients. Fundoscopy revealed typical signs of retinitis pigmentosa (RP) with early-onset macular atrophy. All three MERTK missense variants affect highly conserved residues within functional domains, have low population frequencies and are predicted to be pathogenic in silico.

Conclusions: We report three missense variants in MERTK and present the associated phenotypic data, which are supportive of non-syndromic RP. MERTK is a promising candidate for viral-mediated gene replacement therapy. Moreover, one variant represents a single nucleotide transition, which is theoretically targetable with CRISPR-Cas9 base-editing.

Keywords: CRISPR-Cas; MERTK; Retinitis pigmentosa; gene therapy; mutation.

Figure 1.

Panel A: structure of the MERTK transmembrane protein. The extracellular portion includes two immunoglobulin-like (Ig-like) domains (green) and two fibronectin type III (FN-III) domains (blue). The intracellular region contains a highly conserved kinase domain (yellow). The location of the Three mutations discussed are indicated by red arrows. The respective amino acid residues corresponding to the domains affected are indicated below the protein schematic. Panel B: Conservation across species of the amino acid residue subject to mutation in the c.1133c>t, p.Thr378 met variant (B1), the c.2163t>a, p.His721gln variant (B2) and the c.1866G>C, p.Lys622Asn variant (B3). Panel C: Pedigrees for Case 1 (C1) and Case 2 (C2). Pedigree not available for Case 3. Note the pedigrees are based on clinical presentation and segregation has not been possible.

Figure 2.

Retinal imaging studies for Case 1: (a, b) colour photographs of right and left fundi demonstrating attenuated vessels and waxy disc pallor but not capturing sparse bone spicule pigmentations; (c, d) widefield FAF imaging (55 degrees) demonstrating patchy autofluorescence in the nasal midperiphery and along the supero-temporal arcades; (e, f) OCT imaging showing extensive photoreceptor loss and outer retinal degeneration, with a partially preserved foveal ellipsoid zone.

Figure 3.

Goldmann visual fields for Case 1 (1a) right and (1b) left eyes showing a bilateral residual temporal island as is often seen in advanced RP with a bilateral inferior Scotoma that matches the pattern of degeneration on FAF imaging in Figure 2. Case 2 (2a) right and (2b) left demonstrates generalised, severe visual field constriction with the V4 isopter constricted to approximately 10 degrees in both eyes.

Figure 4.

Retinal imaging for Case 2: (a, b) colour photographs of fundi demonstrating widespread peripheral bone spicule pigmentations and attenuated vessels; (c, d) widefield FAF imaging (55 degrees) demonstrating widespread autofluorescence atrophy and macular atrophy with no ring of increased autofluorescence; (e, f) OCT imaging showing extensive photoreceptor loss, outer retinal degeneration, absence of foveal ellipsoid zone and presence of subretinal material, thought to be secondary to the defective phagocytic process by the RPE.

Figure 5.

Retinal imaging for Case 3: (a, b) colour photographs of fundi demonstrating sparse peripheral pigment migration; (c, d) widefield FAF imaging (55 degrees) showing foveal hyper-autofluorescence; (e, f) OCT imaging showing outer retinal degeneration with some preservation of the foveal ellipsoid zone.