Mutation in the gene GUCA1A, encoding guanylate cyclase-activating protein 1, causes cone, cone-rod, and macular dystrophy.
OBJECTIVE
To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 4-generation family and to examine the phenotype and the degree of intrafamilial variability.


METHODS
Prospective case series.


METHODS
Six affected individuals from a nonconsanguineous British family.


METHODS
Detailed ophthalmologic examination, color fundus photography, autofluorescence imaging, and electrophysiologic assessment were performed. Blood samples were taken for DNA extraction, and mutation screening of GUCA1A, the gene encoding guanylate cyclase-activating protein 1 (GCAP1), was undertaken.


RESULTS
All affected subjects complained of mild photophobia and reduced central and color vision. Onset was between the third and fifth decade, with subsequent gradual deterioration of visual acuity and color vision. Visual acuity ranged between 6/9 and counting fingers. Color vision was either absent or markedly reduced along all 3 color axes. A range of macular appearances was seen, varying from mild retinal pigment epithelial disturbance to extensive atrophy. Electrophysiologic testing revealed a range of electrophysiologic abnormalities: isolated cone electroretinography abnormalities, reduced cone and rod responses (with cone loss greater than rod), and isolated macular dysfunction. The 4 coding exons of GUCA1A were screened for mutations in affected and unaffected family members. A single transition, A319G, causing a nonconservative missense substitution, Tyr99Cys, segregated uniquely in all affected subjects.


CONCLUSIONS
The Tyr99Cys GUCA1A mutation has been previously shown to cause autosomal dominant progressive cone dystrophy. This is the first report of this mutation also causing both cone-rod dystrophy and isolated macular dysfunction. The phenotypic variation described here exemplifies the intrafamilial heterogeneity of retinal dysfunction that can be observed in persons harboring the same mutation and chromosomal segment.
Michaelides
Michel
M
Institute of Ophthalmology, University College London, London, United Kingdom.
Wilkie
Susan E
SE
Jenkins
Sharon
S
Holder
Graham E
GE
Hunt
David M
DM
Moore
Anthony T
AT
Webster
Andrew R
AR
D000328:Adult; D000368:Aged; D002135:Calcium-Binding Proteins / Q000235:genetics*; D003119:Color Perception Tests; D003117:Color Vision Defects / Q000235:genetics; D004252:DNA Mutational Analysis; D004585:Electrooculography; D004596:Electroretinography; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics*; D051604:Guanylate Cyclase-Activating Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology
D002135:Calcium-Binding Proteins; C496736:GUCA1A protein, human; D051604:Guanylate Cyclase-Activating Proteins; D006162:Guanylate Cyclase