A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia.
Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM, and all encode functional components of the phototransduction cascade in cone photoreceptors. Applying a functional-candidate-gene approach that focused on screening additional genes involved in this process in a cohort of 611 index cases with ACHM or other cone photoreceptor disorders, we detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12(∗)) in PDE6H, encoding the inhibitory γ subunit of the cone photoreceptor cyclic guanosine monophosphate phosphodiesterase. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM and preserved short-wavelength-sensitive cone function. Moreover, we show through immunohistochemical colocalization studies in mouse retina that Pde6h is evenly present in all retinal cone photoreceptors, a fact that had been under debate in the past. These findings add PDE6H to the set of genes involved in autosomal-recessive cone disorders and demonstrate the importance of the inhibitory γ subunit in cone phototransduction.
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany. susanne.kohl@uni-tuebingen.de
Susanne
S
Kohl
Frauke
F
Coppieters
Françoise
F
Meire
Simone
S
Schaich
Susanne
S
Roosing
Christina
C
Brennenstuhl
Sylvia
S
Bolz
Maria M
MM
van Genderen
Frans C C
FC
Riemslag
Robert
R
Lukowski
Anneke I
AI
den Hollander
Frans P M
FP
Cremers
Elfride
E
De Baere
Carel B
CB
Hoyng
Bernd
B
Wissinger
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D018389:Codon, Nonsense; D003117:Color Vision Defects / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D018389:Codon, Nonsense; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C576560:PDE6H protein, human