CRB1 mutations in inherited retinal dystrophies

Abstract

Mutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from leber congenital amaurosis (LCA) to rod-cone dystrophy, also called retinitis pigmentosa (RP). Moreover, retinal dystrophies resulting from CRB1 mutations may be accompanied by specific fundus features: preservation of the para-arteriolar retinal pigment epithelium (PPRPE) and retinal telangiectasia with exudation (also referred to as Coats-like vasculopathy). In this publication, we report seven novel mutations and classify over 150 reported CRB1 sequence variants that were found in more that 240 patients. The data from previous reports were used to analyze a potential correlation between CRB1 variants and the clinical features of respective patients. This meta-analysis suggests that the differential phenotype of patients with CRB1 mutations is due to additional modifying factors rather than particular mutant allele combination.

Figure 1

Distribution of CRB1 mutations in the gene and protein. A) Nucleotide numbering is based on cDNA sequence of CRB1 (Ref. NM_201253.2) where A of the ATG initiation codon is 1. The stop and frameshift mutations are indicated above the structure of the gene and the position of the missense mutations are drawn in relation to protein domains. The novel mutations are indicated in red. B) The structures of EGF-like and Ca⁺⁺ binding EGF-like domains with indications of conserved residues and recurrent mutations. The highly conserved cysteine residues are in black, the conserved residues between both domains are in grey and the conserved amino acids specific to the Ca²⁺ binding domain are in blue. C) Evolutionary conservation of the likely pathogenic CRB1 residue changes identified in this work.

Figure 2

Fundus color photographs and Optical Coherence Tomography (OCT). A) Color fundus photograph of the left eye of 3969 showing nummular pigmentary migration in the mid periphery in addition to pigmentary changes within the macula. B) Vertical scan OCT of the left eye of 3969 showing cystic changes in the macular region. C) Color fundus photograph of the right eye of 547 showing bone spicules pigmentary migration in the periphery in addition to atrophic changes within the macula. D) Vertical scan OCT of the right eye of 547 showing atrophic changes in the macular region after resolution of episodes of cystoid changes.

Figure 3

Genotype-phenotype correlation of patients with CRB1 mutations. A) Distribution of CRB1 mutations in LCA, EORD and RP. XY axes represent allele 1 and 2 of the patients, the affected codons serve as xy coordinates, null allele coordinate is designated as 0. The size of the circles is proportional to the number of the CRB1 patients with a given genotype. B) Frequency of null and missense allele combinations in LCA, EORD and RP patients. C) Distribution of CRB1 mutations in patients with/without additional features: PPRPE and Coats-like vasculopathy.