p.Gln200Glu, a putative constitutively active mutant of rod alpha-transducin (GNAT1) in autosomal dominant congenital stationary night blindness.
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p.Gln200Glu, a putative constitutively active mutant of rod alpha-transducin (GNAT1) in autosomal dominant congenital stationary night blindness. / Szabo, Viktoria; Kreienkamp, Hans-Jürgen; Rosenberg, Thomas; Gal, Andreas.
in: HUM MUTAT, Jahrgang 28, Nr. 7, 7, 2007, S. 741-742.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - p.Gln200Glu, a putative constitutively active mutant of rod alpha-transducin (GNAT1) in autosomal dominant congenital stationary night blindness.
AU - Szabo, Viktoria
AU - Kreienkamp, Hans-Jürgen
AU - Rosenberg, Thomas
AU - Gal, Andreas
PY - 2007
Y1 - 2007
N2 - Congenital stationary night blindness (CSNB) is a non-progressive Mendelian condition resulting from a functional defect in rod photoreceptors. A small number of unique missense mutations in the genes encoding various members of the rod phototransduction cascade, e.g. rhodopsin (RHO), cGMP phosphodiesterase beta-subunit (PDE6B), and transducin alpha-subunit (GNAT1) have been reported to cause autosomal dominant (ad) CSNB. While the RHO and PDE6B mutations result in constitutively active proteins, the only known adCSNB-associated GNAT1 change (p.Gly38Asp) produces an alpha-transducin that is unable to activate its downstream effector molecule in vitro. In a multigeneration Danish family with adCSNB, we identified a novel heterozygous C to G transversion (c.598C>G) in exon 6 of GNAT1 that should result in a p.Gln200Glu substitution in the evolutionarily highly conserved Switch 2 region of alpha-transducin, a domain that has an important role in binding and hydrolyzing GTP. Computer modeling based on the known crystal structure of transducin suggests that the p.Gln200Glu mutant exhibits impaired GTPase activity, and thereby leads to constitutive activation of phototransduction. This assumption is in line with our results of trypsin protection assays as well as previously published biochemical data on mutants of this glutamine in the GTPase active site of alpha-transducin following in vitro expression, and observations that inappropriately activating mutants of various members of the rod phototransduction cascade represent one of the major molecular causes of adCSNB.
AB - Congenital stationary night blindness (CSNB) is a non-progressive Mendelian condition resulting from a functional defect in rod photoreceptors. A small number of unique missense mutations in the genes encoding various members of the rod phototransduction cascade, e.g. rhodopsin (RHO), cGMP phosphodiesterase beta-subunit (PDE6B), and transducin alpha-subunit (GNAT1) have been reported to cause autosomal dominant (ad) CSNB. While the RHO and PDE6B mutations result in constitutively active proteins, the only known adCSNB-associated GNAT1 change (p.Gly38Asp) produces an alpha-transducin that is unable to activate its downstream effector molecule in vitro. In a multigeneration Danish family with adCSNB, we identified a novel heterozygous C to G transversion (c.598C>G) in exon 6 of GNAT1 that should result in a p.Gln200Glu substitution in the evolutionarily highly conserved Switch 2 region of alpha-transducin, a domain that has an important role in binding and hydrolyzing GTP. Computer modeling based on the known crystal structure of transducin suggests that the p.Gln200Glu mutant exhibits impaired GTPase activity, and thereby leads to constitutive activation of phototransduction. This assumption is in line with our results of trypsin protection assays as well as previously published biochemical data on mutants of this glutamine in the GTPase active site of alpha-transducin following in vitro expression, and observations that inappropriately activating mutants of various members of the rod phototransduction cascade represent one of the major molecular causes of adCSNB.
M3 - SCORING: Zeitschriftenaufsatz
VL - 28
SP - 741
EP - 742
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 7
M1 - 7
ER -