Electrophysiologic and phenotypic features of an autosomal cone-rod dystrophy caused by a novel CRX mutation☆
Section snippets
Subjects
This article is based on a clinical and molecular reexamination of four generations of a large Albertan kindred whose phenotype was initially described by Pearce1 in 1975 as a progressive autosomal dominant cone dystrophy. Ongoing ophthalmic examination has since allowed better characterization of the disease course in this family. Twenty-nine individuals were clinically reexamined in this study, 23 of whom also participated in the DNA mapping analysis. An additional two spouses with normal
Results
Reexamination of affected individuals within this family presents a redefined clinical picture of progressive adCRD. Measures of bilateral visual acuity and color discrimination are presented along with the pedigree and individual disease status assignments in Table 1 and Figure 1. Age of onset varied significantly in the cases studied, ranging approximately between the second and sixth decades. Acuity changes and macular degeneration were preceded by nyctalopia and/or reduced color
Discussion
The variable phenotype of this family was originally thought to consist of two discrete, coincident monogenic disorders (dominant macular dystrophy alongside a generalized tapetoretinal dystrophy).1 Here we have demonstrated RP-like retinal atrophy to be the endpoint of the phenotypic progression of this disease and have demonstrated the identity of this phenotype with adCRD2 as reported for other dominant mutations in CRX.6, 7, 11 In addition, this study underscores the clinical value of
Acknowledgements
The skillful assistance of Dr. W. G. Pearce in the original identification and investigation of this family is gratefully acknowledged. We also thank and acknowledge the patients and family members whose willing participation made this study possible.
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Cited by (27)
Pathogenicity discrimination and genetic test reference for CRX variants based on genotype-phenotype analysis
2019, Experimental Eye ResearchCRX variants in cone-rod dystrophy and mutation overview
2012, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The digested amplicons were separated by electrophoresis on a 10% polyacrylamide gel and the results were visualized with silver staining. CRX mutations detected in this study and those mutations reported previously as well as the associated phenotypes were reviewed and summarized based on previous reports [2,5,6,9–42]. Sequencing analysis identified three heterozygous variants in CRX in 3 of 130 probands with CORD, respectively, including c.239A>G (p.Glu80Gly) in family QT470, c.362C>T (p.Ala121Val) in family QT70, and c.335C>T (p.Ala112Val) in family QT22 (Table 1 and Fig. 1).
Proteolytic cleavage of ataxin-7 by caspase-7 modulates cellular toxicity and transcriptional dysregulation
2007, Journal of Biological ChemistryCitation Excerpt :Indeed, characterization of the ataxin-7 protein revealed a polyQ-dependent interaction with the cone-rod homeobox protein (Crx), a photoreceptor specific transcriptional factor (25, 33). In SCA7 knock-in and transgenic mice, retinal-specific genes are down-regulated and contribute to disease progression (25, 32, 33). Ataxin-7 is also a member of the STAGA complex.
Genotype-Phenotype Correlation in a German Family with a Novel Complex CRX Mutation Extending the Open Reading Frame
2007, OphthalmologyCitation Excerpt :Twenty-five of these mutations can be extracted from the literature (http://www.retina-international.org/sci-news/crxmut.htm [update from June 16, 2005]). Phenotypic and genetic data were extracted from the published cases.3,4,15–34 Patients were evaluated for BCVA as the most completely reported measure.
The Clinical Applications of Multifocal Electroretinography: A Systematic Review
2007, Survey of OphthalmologyCitation Excerpt :Because mfERG can provide an objective measurement of central cone function, it is particularly useful in the assessment of cone dystrophy.80,93,131,149,152,154,169,282 The main mfERG findings in patients with cone dystrophy include severe reductions in response amplitudes with delays in implicit times or complete absence of mfERG responses, especially in the central retina.93,131,152,154,169,282 Holopigian et al evaluated both the cone- and rod-mediated mfERG in patients with cone dystrophy.93
Progressive Cone and Cone-Rod Dystrophies: Phenotypes and Underlying Molecular Genetic Basis
2006, Survey of OphthalmologyCitation Excerpt :These findings suggest that successful gene therapy in patients with photoreceptor defects may ultimately depend upon intervention in early stages of disease and upon accurate control of transgene expression.174 A similar severe early onset AD-CORD phenotype associated with CRX mutations (cone–rod homeobox-containing gene) has been reported in patients of diverse origin including British, Greek, Japanese, and Canadian families.42,43,69,70,97,147 Loss of visual acuity occurs in the first decade of life, onset of night blindness occurs after 20 years of age, and little or no visual function remains after the age of 50 years.
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Supported by the University of Alberta Hospitals Foundation, Edmonton, Alberta, Canada.