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Jean-Michel Rozet, Isabelle Perrault, Sylvie Gerber, Sylvain Hanein, Fabienne Barbet, Dominique Ducroq, Eric Souied, Arnold Munnich, Josseline Kaplan; Complete Abolition of the Retinal-Specific Guanylyl Cyclase (retGC-1) Catalytic Ability Consistently Leads to Leber Congenital Amaurosis (LCA). Invest. Ophthalmol. Vis. Sci. 2001;42(6):1190-1192.
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purpose. Leber congenital amaurosis (LCA) is the earliest and the most severe
form of all inherited retinal dystrophies. In 1996, the current
investigators ascribed the disease in families linked to the LCA1 locus on chromosome 17p13.1 to mutations in
the photoreceptor-specific guanylyl cyclase (retGC-1)
gene. So far, 22 different mutations, of which 11 are missense
mutations, have been identified in 25 unrelated families. This is a
report of the functional analyses of nine of the missense mutations.
methods. cDNA constructs were generated that contained the retGC-1 missense mutations identified in patients
related to the LCA1 locus. Mutants were expressed in
COS7 cells and assayed for their ability to hydrolyze guanosine
triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).
results. All mutations lying in the catalytic domain showed a complete abolition
of cyclase activity. In contrast, only one mutation lying in the
extracellular domain also resulted in a severely reduced catalytic
activity, whereas the others showed completely normal activity.
conclusions. More than half the mutations identified in patients related to the LCA1 locus are truncating mutations expected to result
in a total abolition of retGC-1 activity. Concerning missense
mutations, half of them lying in the catalytic domain of the protein
also result in the complete inability of the mutant cyclases to
hydrolyze GTP into cGMP in vitro. In contrast, missense mutations lying
in the extracellular domain, except one affecting the initiation codon,
showed normal catalytic activity of retGC-1. Nevertheless, considering
that all patients related to the LCA1 locus displayed
the same phenotype, it can be assumed that all missense mutations would
have the same dramatic consequences on protein activity in vivo as
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