Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders.
Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.
Thiadens
Alberta A H J
AA
Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, The Netherlands.
den Hollander
Anneke I
AI
Roosing
Susanne
S
Nabuurs
Sander B
SB
Zekveld-Vroon
Renate C
RC
Collin
Rob W J
RW
De Baere
Elfride
E
Koenekoop
Robert K
RK
van Schooneveld
Mary J
MJ
Strom
Tim M
TM
van Lith-Verhoeven
Janneke J C
JJ
Lotery
Andrew J
AJ
van Moll-Ramirez
Norka
N
Leroy
Bart P
BP
van den Born
L Ingeborgh
LI
Hoyng
Carel B
CB
Cremers
Frans P M
FP
Klaver
Caroline C W
CC
D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D003117:Color Vision Defects / Q000235:genetics*; D003241:Consanguinity; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017949:Retinal Cone Photoreceptor Cells / Q000201:enzymology* / Q000502:physiology
D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C096885:PDE6C protein, human