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Stephanie A. Hagstrom, Michael Adamian, Michael Scimeca, Basil S. Pawlyk, Guohua Yue, Tiansen Li; A Role for the Tubby-Like Protein 1 in Rhodopsin Transport. Invest. Ophthalmol. Vis. Sci. 2001;42(9):1955-1962.
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purpose. To test the hypothesis that a lack of Tubby-like protein 1 (TULP1)
function causes aberrant transport of nascent rhodopsin and to examine
the functional relationship between the homologous proteins TULP1 and
Tubby by studying mice carrying combined mutations.
methods. Subcellular localization of TULP1 and rhodopsin in photoreceptors was
determined by immunofluorescence and by postembedding immunoelectron
microscopy. Mice carrying different tulp1/tubby allele
combinations were examined by histology, electroretinograms (ERGs), and
results. TULP1 is distributed throughout the photoreceptor cytoplasm but is
excluded from the outer segments and the nuclei. In the tulp1−/− mice, ectopic accumulation of rhodopsin
occurs at an early age. Both the vesicular profiles in the
interphotoreceptor space and the inner segment plasma membranes are
immunoreactive for rhodopsin. Mice doubly homozygous for null mutations in the tulp1 and tubby genes initially develop photoreceptors and express
a battery of photoreceptor markers at age 14 days. Thereafter their
photoreceptors undergo a fulminant degeneration that reaches completion
by postnatal day 17. The disease phenotype in the double homozygote is
much more severe than either single homozygote. Double heterozygotes
are phenotypically normal.
conclusions. A lack of TULP1 function results in misrouting of nascent rhodopsin.
TULP1 may be a component of the cellular machinery that targets nascent
rhodopsin to the outer segments. Comparison of disease phenotypes in
the single and double mutants suggests that TULP1 and Tubby are not
functionally interchangeable in photoreceptors nor do they form an
obligate functional complex.
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