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Decreased catalytic...
Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia
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Grau, Tanja (author)
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Artemyev, Nikolai O. (author)
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Rosenberg, Thomas (author)
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Dollfus, Helene (author)
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Haugen, Olav H. (author)
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Sener, E. Cumhur (author)
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Jurklies, Bernhard (author)
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- Andréasson, Sten (author)
- Lund University,Lunds universitet,Oftalmologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Ophthalmology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine
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Kernstock, Christoph (author)
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Larsen, Michael (author)
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Zrenner, Eberhart (author)
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Wissinger, Bernd (author)
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Kohl, Susanne (author)
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(creator_code:org_t)
- 2010-12-01
- 2011
- English.
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:4, s. 719-730
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http://dx.doi.org/10...
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Abstract
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- Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional characterization of six missense mutations applying the baculovirus system to express recombinant mutant and wildtype chimeric PDE6C/PDE5 proteins in Sf9 insect cells. Purified proteins were analyzed using Western blotting, phosphodiesterase (PDE) activity measurements as well as inhibition assays by zaprinast and P gamma. Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles. For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively. We also observed differences for P gamma inhibition. The p.E790K mutant, with an IC50 value of 2.7 nM is 20.7-fold more sensitive for P gamma inhibition, whereas the p.Y323N mutant with an IC50 of 158 nM is 3-fold less sensitive when compared with the wildtype control.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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- By the author/editor
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Grau, Tanja
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Artemyev, Nikola ...
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Rosenberg, Thoma ...
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Dollfus, Helene
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Haugen, Olav H.
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Sener, E. Cumhur
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show more...
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Jurklies, Bernha ...
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Andréasson, Sten
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Kernstock, Chris ...
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Larsen, Michael
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Zrenner, Eberhar ...
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Wissinger, Bernd
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Kohl, Susanne
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Human Molecular ...
- By the university
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Lund University