Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy.
OBJECTIVE
To investigate whether the major achromatopsia genes (CNGA3 and CNGB3) play a role in the cause of progressive cone dystrophy (CD).


METHODS
Prospective multicenter study.


METHODS
Probands (N = 60) with autosomal recessive (ar) CD from various ophthalmogenetic clinics in The Netherlands.


METHODS
All available ophthalmologic data from the arCD probands were registered from medical charts and updated by an additional ophthalmologic examination. Mutations in the CNGA3 and CNGB3 genes were analyzed by direct sequencing.


METHODS
CNGA3 and CNGB3 mutations and clinical course in arCD probands.


RESULTS
In 3 arCD probands (3/60; 5%) we found 2 mutations in the CNGB3 gene. Two of these probands had compound heterozygous mutations (p.R296YfsX9/p.R274VfsX12 and p.R296YfsX9/c.991-3T>g). The third proband revealed homozygous missense mutations (p.R403Q) with 2 additional variants in the CNGA3 gene (p.E228K and p.V266M). These probands did not have a congenital nystagmus, but had a progressive deterioration of visual acuity, color vision, and photopic electroretinogram, with onset in the second decade. In 6 other unrelated probands, we found 6 different heterozygous amino acid changes in the CNGA3 (N = 4) and CNGB3 (N = 2) gene.


CONCLUSIONS
The CNGB3 gene accounts for a small fraction of the later onset progressive form of cone photoreceptor disorders, and CNGA3 may have an additive causative effect. Our data indicate that these genes are involved in a broader spectrum of cone dysfunction, and it remains intriguing why initial cone function can be spared despite similar gene defects.


BACKGROUND
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Thiadens
Alberta A H J
AA
Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Roosing
Susanne
S
Collin
Rob W J
RW
van Moll-Ramirez
Norka
N
van Lith-Verhoeven
Janneke J C
JJ
van Schooneveld
Mary J
MJ
den Hollander
Anneke I
AI
van den Born
L Ingeborgh
LI
Hoyng
Carel B
CB
Cremers
Frans P M
FP
Klaver
Caroline C W
CC
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D003119:Color Perception Tests; D003117:Color Vision Defects / Q000175:diagnosis / Q000235:genetics*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D014792:Visual Acuity / Q000502:physiology
C518238:CNGA3 protein, human; C415904:CNGB3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels