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Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders

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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 a 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.
Keywords
KCNV2, CNGB3, PROGRESSIVE CONE, AUTOSOMAL RECESSIVE CONE, ROD DYSTROPHIES, RPGR EXON, GENE, DEGENERATION, ACHROMATOPSIA, ZEBRAFISH

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Chicago
Thiadens, Alberta AHJ, Anneke I den Hollander, Susanne Roosing, Sander B Nabuurs, Renate C Zekveld-Vroon, Rob WJ Collin, Elfride De Baere, et al. 2009. “Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-onset Cone Photoreceptor Disorders.” American Journal of Human Genetics 85 (2): 240–247.
APA
Thiadens, A. A., den Hollander, A. I., Roosing, S., Nabuurs, S. B., Zekveld-Vroon, R. C., Collin, R. W., De Baere, E., et al. (2009). Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. AMERICAN JOURNAL OF HUMAN GENETICS, 85(2), 240–247.
Vancouver
1.
Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, et al. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. AMERICAN JOURNAL OF HUMAN GENETICS. 2009;85(2):240–7.
MLA
Thiadens, Alberta AHJ, Anneke I den Hollander, Susanne Roosing, et al. “Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-onset Cone Photoreceptor Disorders.” AMERICAN JOURNAL OF HUMAN GENETICS 85.2 (2009): 240–247. Print.
@article{940969,
  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 a 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.},
  author       = {Thiadens, Alberta AHJ and den Hollander, Anneke I and Roosing, Susanne and Nabuurs, Sander B and Zekveld-Vroon, Renate C and Collin, Rob WJ and De Baere, Elfride and Koenekoop, Robert K and van Schooneveld, Mary J and Strom, Tim M and van Lith-Verhoeven, Janneke JC and Lotery, Andrew J and van Moll-Ramirez, Norka and Leroy, Bart and van den Born, L Ingeborgh and Hoyng, Carel B and Cremers, Frans PM and Klaver, Caroline CW},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  language     = {eng},
  number       = {2},
  pages        = {240--247},
  title        = {Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2009.06.016},
  volume       = {85},
  year         = {2009},
}

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