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Samuel G. Jacobson, Artur V. Cideciyan, Alessandro Iannaccone, Richard G. Weleber, Gerald A. Fishman, Albert M. Maguire, Louisa M. Affatigato, Jean Bennett, Eric A. Pierce, Michael Danciger, Debora B. Farber, Edwin M. Stone; Disease Expression of RP1 Mutations Causing Autosomal Dominant Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2000;41(7):1898-1908.
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purpose. To determine the disease expression in heterozygotes for mutations in
the RP1 gene, a newly identified cause of autosomal
dominant retinitis pigmentosa (adRP).
methods. Screening strategies were used to detect disease-causing mutations in
the RP1 gene, and detailed studies of phenotype were
performed in a subset of the detected RP1 heterozygotes
using electroretinography (ERG), psychophysics, and optical coherence
results. Seventeen adRP families had heterozygous RP1 changes.
Thirteen families had the Arg677ter mutation, whereas four others had
one of the following: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763
(5-bp del), and Tyr1053 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal variation in disease, with
the far peripheral inferonasal retina being most vulnerable; central
and superior temporal retinal regions were better preserved. The
earliest manifestation of disease was rod dysfunction, detectable as
reduced rod ERG photoresponse maximum amplitude, even in heterozygotes
with otherwise normal clinical, functional, and OCT cross-sectional
retinal imaging results. At disease stages when cone abnormalities were
present, there was greater rod than cone dysfunction. Patients with the RP1 frameshift mutations showed similarities in phenotype to
those with the Arg677ter mutation.
conclusions. Earliest disease expression of RP1 gene mutations causing
adRP involves primarily rod photoreceptors, and there is a gradient of
vulnerability of retinopathy with more pronounced effects in the
inferonasal peripheral retina. At other disease stages, cone function
is also affected, and severe retina-wide degeneration can occur. The
nonpenetrance or minimal disease expression in some Arg677ter
mutation-positive heterozygotes suggests important roles for modifier
genes or environmental factors in RP1-related
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