May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Cone Phosphodiesterase Defects in the Murine cpfl1 Mutant and Human Achromatopsia Patients
Author Affiliations & Notes
  • B. Wissinger
    Molecular Genetics Laboratory, University Eye Hospital, Tuebingen, Germany
  • B. Chang
    The Jackson Laboratories, Bar Harbor, Maine
  • S. Dangel
    Molecular Genetics Laboratory, University Eye Hospital, Tuebingen, Germany
  • N. Hawes
    The Jackson Laboratories, Bar Harbor, Maine
  • R. Hurd
    The Jackson Laboratories, Bar Harbor, Maine
  • B. Jurklies
    University Eye Hospital, Essen, Germany
  • E. C. Sener
    University Eye Hospital, Ankara, Turkey
  • S. Andreasson
    University Eye Hospital, Lund, Sweden
  • S. Kohl
    Molecular Genetics Laboratory, University Eye Hospital, Tuebingen, Germany
  • J. R. Heckenlively
    Kellogg Eye Center, Ann Arbor, Michigan
  • Footnotes
    Commercial Relationships B. Wissinger, None; B. Chang, None; S. Dangel, None; N. Hawes, None; R. Hurd, None; B. Jurklies, None; E.C. Sener, None; S. Andreasson, None; S. Kohl, None; J.R. Heckenlively, None.
  • Footnotes
    Support DFG Wi1189/6-3, DFG KFG134, NIH EY07758
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 4521. doi:
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      B. Wissinger, B. Chang, S. Dangel, N. Hawes, R. Hurd, B. Jurklies, E. C. Sener, S. Andreasson, S. Kohl, J. R. Heckenlively; Cone Phosphodiesterase Defects in the Murine cpfl1 Mutant and Human Achromatopsia Patients. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4521.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: The cone photoreceptor function loss 1 (cpfl1) mutant is a spontaneous mouse mutant identified at the Jackson Lab. This study addresses the retinal function and retinal morphology of the cpfl1 mutant and the identification of its genetic basis. In comparison we report the clinical and genetic findings in human achromatopsia patients with homologous genetic defects.

Methods:: ERG recordings were obtained from cpfl1 mice and their retinae were studied histologically. Whole genome linkage mapping of the cpfl1 trait was done applying microsatellite markers. Mutation screening and analysis was done by DNA sequencing of genomic PCR or RT-PCR products and Southern blotting. Putative splice site mutations were analyzed using a heterologous splicing assay. Achromatopsia patients underwent ophthalmological examination including photopic, scotopic and MfERG recordings, color vision testing, and funduscopy.

Results:: cpfl1 mice are characterized by a lack of cone function and a rapid progressive loss of cone photoreceptors. We mapped the cpfl1 locus to a narrow interval of 0.7 cM on mouse chromosome 19 and subsequently identified pathogenic mutations in the pde6c gene, that encodes the katalytic subunit of the cone photoreceptor phosphodiesterase.Based on linkage mapping and candidate gene analysis we were able to identify 3 achromatopsia families that segregate PDE6C mutations. These include missense mutations, stop mutations and splice site mutations. The latter were confirmed by in vitro splicing assays. Patients with PDE6C mutations clinically presented as typical achromats. Some provided evidence of an early progressive disease course.

Conclusions:: cpfl1 is caused by mutations in pde6c and represent a homologous mouse model for a rare form of human achromatopsia. PDE6C is the fourth gene now associated with achromatopsia in humans.

Keywords: retinal degenerations: hereditary • retina: distal (photoreceptors, horizontal cells, bipolar cells) • gene mapping 
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