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Mutations in the GUCA1A gene involved in hereditary cone dystrophies impair calcium‐mediated regulation of guanylate cyclase
Author(s) -
Kitiratschky Veronique B.D.,
Behnen Petra,
Kellner Ulrich,
Heckenlively John R,
Zrenner Eberhart,
Jägle Herbert,
Kohl Susanne,
Wissinger Bernd,
Koch KarlWilhelm
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21055
Subject(s) - mutant , biology , gucy2d , mutation , gene , guanylate cyclase , guanylate cyclase 2c , microbiology and biotechnology , gucy1b3 , gucy1a3 , genetics , receptor
The GUCA1A gene encodes the guanylate cyclase activating protein 1 (GCAP1) of mammalian rod and cone photoreceptor cells, which is involved in the Ca 2+ ‐dependent negative feedback regulation of membrane bound guanylate cyclases in the retina. Mutations in the GUCA1A gene have been associated with different forms of cone dystrophies leading to impaired cone vision and retinal degeneration. Here we report the identification of three novel and one previously detected GUCA1A mutations: c.265G>A (p.Glu89Lys), c.300T>A (p.Asp100Glu), c.476G>T (p.Gly159Val) and c.451C>T (p.Leu151Phe). The clinical data of the patients carrying these mutations were compared with the functional consequences of the mutant GCAP1 forms. For this purpose we purified the heterologously expressed GCAP1 forms and investigated whether the mutations affected the Ca 2+ ‐triggered conformational changes and the apparent interaction affinity with the membrane bound guanylate cyclase. Furthermore, we analyzed Ca 2+ ‐dependent regulatory modes of wildtype and mutant GCAP1 forms. Although all novel mutants were able to act as a Ca 2+ ‐sensor protein, they differed in their Ca 2+ ‐dependent activation profiles leading to a persistent stimulation of guanylate cyclase activities at physiological intracellular Ca 2+ concentration. © 2009 Wiley‐Liss, Inc.