title: Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Alberta A H J
authors.initials: AA
authors.lastname: Thiadens
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.forename: Sander B
authors.initials: SB
authors.lastname: Nabuurs
authors.forename: Renate C
authors.initials: RC
authors.lastname: Zekveld-Vroon
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Mary J
authors.initials: MJ
authors.lastname: van Schooneveld
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Janneke J C
authors.initials: JJ
authors.lastname: van Lith-Verhoeven
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
authors.forename: Norka
authors.initials: N
authors.lastname: van Moll-Ramirez
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
mesh_terms: 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
chemical_list: D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C096885:PDE6C protein, human