Pigmented Paravenous Chorioretinal Atrophy Is Associated with a Mutation within the Crumbs Homolog 1 ( CRB1 ) Gene

Ophthalmic Research Centre, Institute of Clinical Science, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.4). 02/2005; 46(1):322-8. DOI: 10.1167/iovs.04-0734
Source: PubMed


Pigmented paravenous chorioretinal atrophy (PPCRA) is an unusual retinal degeneration characterized by accumulation of pigmentation along retinal veins. The purpose of this study was to describe the phenotype of a family with PPCRA, determine the mode of inheritance, and identify the causal mutation.
Ophthalmic examination was performed on seven family members and serially detailed in the proband over a 3-year period. Blood samples were collected and DNA extracted. All 12 coding exons and the 5' promoter region of the crumbs homologue 1 (CRB1) gene were PCR amplified and DNA sequenced. In silico homology modeling was performed on the mutated protein domain.
Subtle symmetrical chorioretinal atrophy in the inferior quadrant was the earliest clinical sign detectable within this family. Paravenous pigmentation occurred initially in the far periphery, progressing centrally, with atrophy later becoming more widespread, involving the nasal, then the temporal, and finally the upper quadrant. A novel, dominant Val162Met mutation within the fourth EGF-like domain of CRB1 cosegregates with the PPCRA phenotype. It is thought to affect domain structure, because codon 162 is involved in hydrogen bonding between the antiparallel beta-strands of the major beta-sheet, causing sufficient perturbation of the backbone that the domain-stabilizing hydrogen bond does not form or is weakened.
PPCRA was dominantly inherited in this family, but exhibited variable expressivity. Males are more likely to exhibit a severe phenotype, whereas females may remain virtually asymptomatic even in later years. The PPCRA phenotype is associated with a Val162Met mutation in CRB1 which is likely to affect the structure of the CRB1 protein.

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    • "Mutations in the Crumbs homolog 1 (CRB1) gene are known to cause retinitis pigmentosa-12 (RP-12) [1] and Leber congenital amaurosis 8 (LCA8) [2]. A CRB1 mutation was also reported in a family with possible autosomal dominant inherited pigmented paravenous chorioretinal atrophy (PPCRA) [3], but this was not verified by other studies. RP is caused by progressive loss of rod and cone photoreceptors. "
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    ABSTRACT: To identify disease-causing mutations in Chinese families who presented with retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). The pathogenic variant in a Chinese family with autosomal dominant RP was investigated with a specific hereditary eye disease enrichment panel (HEDEP) based on targeted exome capture technology. The identified variant was confirmed with Sanger sequencing. CRB1 mutations in 67 patients with sporadic retinal dystrophy were examined with Sanger sequencing. Compound heterozygous mutations were identified in a family who had undergone HEDEP analysis. After complete sequence analysis of the CRB1 gene was performed in 67 patients with sporadic retinal dystrophy, other compound heterozygous mutations were detected in three families. The mutations included three novel heterozygous mutations: c.3059delT (p.M1020SfsX1), c.3460T>A (p.C1154S), and c.4207G>C (p.E1403Q). The mutation frequency of CRB1 in this study was 5.9% (8/136). Our findings broaden the spectrum of CRB1 mutations and the phenotypic spectrum of the disease in Chinese patients. The results from this study show that patients with LCA carry CRB1 null mutations more frequently than patients with RP.
    Molecular vision 03/2014; 20:359-67. · 1.99 Impact Factor
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    • "Mutations in Crumbs homologue 1 (CRB1; OMIM 600105) have been associated with several visual disorders including retinitis pigmentosa (RP) with [10,11] or without [11,12] preserved para-arteriolar retinal pigment epithelium, paravenous pigmented chorioretinal atrophy [13], and LCA [14,15]. Of these disorders, LCA is the most severe form of inherited retinal dystrophy and is characterized by severe visual impairment from birth or very early in infancy and a decreased or absent electroretinogram (ERG) response [16]. "
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    ABSTRACT: Leber congenital amaurosis (LCA) is one of the most severe inherited retinal dystrophies with the earliest age of onset. Mutations in the Crumbs homologue 1 (CRB1; OMIM 600105) gene explain 10%-24% of cases with LCA depending on the population. The aim of the present work was to study a fetal mutation associated to LCA in maternal plasma by a new methodology in the noninvasive prenatal diagnosis field: the denaturing High Performance Liquid Chromatography (dHPLC). This study presents the case of a compound heterozygous fetus for two mutations in CRB1 (1q3.1-q32.2). dHPLC and automated DNA sequencing were used to detect the paternally inherited fetal mutation in a maternal plasma sample collected at the 12th week of gestation. To test the detection limit of dHPLC, we made serial dilutions of paternal DNA in control DNA. We were able to detect the presence of the paternally inherited fetal CRB1 mutation in maternal plasma by dHPLC. Moreover, by comparing chromatograms of serial dilutions to the plasma sample, we could ascertain that the percentage of fetal DNA in maternal plasma was at least 2%. However, the detection of the fetal mutation was not possible by automated DNA sequencing. dHPLC seems to be sensitive enough to detect small amounts of fetal DNA in maternal plasma samples. It could be a useful tool for the noninvasive prenatal detection of paternally inherited point mutations associated with retinopathies.
    Molecular vision 02/2008; 14:1388-94. · 1.99 Impact Factor
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    ABSTRACT: Leber congenital amaurosis ([LCA], MIM 204000) is an important, currently untreatable congenital retinal dystrophy that inexorably leads to blindness. Its importance is twofold and lies in the fact that it creates a tremendous burden on the affected child, the family, and society, as the blindness is life long and commences at birth. Also, LCA gene discoveries have led to an increased understanding of the molecular determinants of retinal physiology and retinal development by identifying new biochemical and cellular pathways. Therefore, LCA serves as a model for all human retinal dystrophies and human retinal development and physiology. LCA has a worldwide prevalence of 3 in 100,000 newborns and accounts for 5% or more of all inherited retinopathies and approx 20% of children attending schools for the blind (1). We estimate that 180,000 patients are affected worldwide (2). Leber defined LCA in 1869 as a congenital form of retinitis pigmentosa (RP) with profound visual loss at birth, nystagmus, amaurotic pupils, and a pigmentary retinopathy (3). A severely reduced electroretinogram (ERG) was added to the definition as this distinguishes it from a complex set of overlapping retinal dystrophies (4).
    Journal of Neuro-Ophthalmology 08/1987; 7(3):178. DOI:10.1007/978-1-59745-186-4_3 · 1.95 Impact Factor
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