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Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene
S G Jacobson1, A V Cideciyan, Y Huang
1Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia 19104, USA.
Purpose:
To define the phenotypes of retinal degenerations associated with mutations in the gene encoding CRX (cone-rod homeobox), a photoreceptor-specific transcription factor.
Methods:
Heterozygotes with the E168 [delta1 bp], E168 [delta2 bp], or G217 [delta1 bp] CRXgene mutation were studied clinically, with visual function tests, including rod and cone perimetry and electroretinography (ERG), and with optical coherence tomography (OCT).
Results:
Clinical diagnoses included autosomal dominant cone-rod dystrophy in one family (E168 [delta1 bp] mutation) and simplex Leber congenital amaurosis in two families (E168 [delta2 bp], G217 [delta1 bp] mutations). In the family with the E168 [delta1 bp] mutation, two siblings had relatively mild disease expression in the third decade of life. The central retinas of these two patients had profound loss of rod and short wavelength cone function; long/middle wavelength cone thresholds were elevated at fixation, but there were greater paracentral than central abnormalities. Peripheral retinal dysfunction was evident by psychophysics and by maximum amplitude loss for rod- and cone-isolated ERG photoreceptor responses. OCT cross-sectional reflectance images showed decreased central retinal thickness consistent with photoreceptor loss. An additional member of this family (E168 [delta1 bp] mutation) and two other patients (representing E168 [delta2 bp] and G217 [delta1 bp] mutations) had a severe phenotype with retina-wide loss of function and islands of function remaining only in the temporal periphery.
Conclusions:
Truncation mutations in CRX are associated with retinopathies that share phenotypic features but vary in disease severity. The disease mechanism could involve abnormal photoreceptor development compounded by a disturbance in the maintenance of photoreceptors in the mature retina.
Insights
Mutations in the CRX gene cause retinal degenerations like cone-rod dystrophy and Leber congenital amaurosis, with varying severity. These genetic defects impact photoreceptor development and maintenance.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- The CRX (cone-rod homeobox) gene encodes a crucial photoreceptor-specific transcription factor.
- Mutations in CRX are implicated in various inherited retinal diseases.
Purpose of the Study:
- To characterize the clinical phenotypes of retinal degenerations caused by specific CRX gene mutations.
- To investigate the relationship between CRX mutations and disease severity.
Main Methods:
- Clinical examination of patients with E168 [delta1 bp], E168 [delta2 bp], or G217 [delta1 bp] CRX gene mutations.
- Visual function testing including perimetry and electroretinography (ERG).
- Optical coherence tomography (OCT) for retinal structure assessment.
Main Results:
- Identified autosomal dominant cone-rod dystrophy and simplex Leber congenital amaurosis associated with CRX mutations.
- Observed variable disease severity, ranging from mild to severe retina-wide dysfunction.
- OCT revealed decreased central retinal thickness, indicating photoreceptor loss.
Conclusions:
- Truncation mutations in CRX lead to retinopathies with shared features but differing severity.
- The underlying mechanism may involve impaired photoreceptor development and maintenance.