A role for the tubby-like protein 1 in rhodopsin transport

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 mi croscopy. Mice carrying different tulp1/tubby, allele combinations were exa mined by histology, electroretinograms (ERGS), and immunofluorescence micro scopy. RESULTS. TULP1 is distributed throughout the photoreceptor cytoplasm but is excluded from the outer segments and the nuclei. In the tulp1-/- mice, ect opic accumulation of rhodopsin occurs at an early age. Both the Vesicular p rofiles in the interphotoreceptor space and the inner segment plasma membra nes are immunoreactive for rhodopsin. Mice doubly homozygous for null mutat ions in the tulp1 and tubby genes initially develop photoreceptors and expr ess a battery of photoreceptor markers at age 14 days. Thereafter their pho toreceptors undergo a fulminant degeneration that reaches completion by pos tnatal day 17. The disease phenotype in the double homozygote is much more severe than either single homozygote. Double heterozygotes are phenotypical ly normal. CONCLUSIONS. A lack of TULP1 function results in misrouting of nascent rhod opsin. TULP1 may be a component of the cellular machinery that targets nasc ent rhodopsin to the outer segments. Comparison of disease phenotypes in th e single and double mutants suggests that TULP1 and Tubby are not functiona lly interchangeable in photoreceptors nor do they form an obligate function al complex.