Dominant Negative Mechanism Underlies Autosomal Dominant Stargardt-like Macular Dystrophy Linked to Mutations in ELOVL4

ELOVL4 (elongation of very long chain fatty acids 4) is a member of the ELO family of proteins involved in the biosynthesis of very long chain fatty acids. Protein truncation mutations in ELOVL4 have been identified in patients with autosomal dominant Stargardt-like macular degeneration. To determine whether a dominant negative mechanism is responsible for the autosomal dominant inheritance pattern of this disease, we studied the subcellular localization and interaction of wild type and mutant ELOVL4 in COS-7 and HEK 293T cultured cells by immunofluorescence and co-immunoprecipitation. Wild type ELOVL4 containing an endoplasmic reticulum retention sequence was localized to the endoplasmic reticulum as expected. In contrast, disease-associated C-terminal truncation ELOVL4 mutants accumulated as large inclusions exhibiting aggresome-like characteristics in a juxtanuclear position within COS-7 cells. When the wild type and mutant proteins were co-expressed incultured cells, wild type ELOVL4 co-purified with mutant ELOVL4 on an immunoaffinity column and co-localized with the mutant protein in aggresome-like inclusions adjacent to the nucleus. These results indicate that wild type and mutant ELOVL4 form a complex that exhibits an abnormal subcellular localization found for individually expressed mutant ELOVL4. From these studies, we conclude that disease-linked C-terminal truncation mutants of ELOVL4 exert a dominant negative effect on wild type ELOVL4, altering its subcellular localization. This dominant negative mechanism contributes to the autosomal dominant inheritance of Stargardt-like macular dystrophy. ELOVL4 (elongation of very long chain fatty acids 4) is a member of the ELO family of proteins involved in the biosynthesis of very long chain fatty acids. Protein truncation mutations in ELOVL4 have been identified in patients with autosomal dominant Stargardt-like macular degeneration. To determine whether a dominant negative mechanism is responsible for the autosomal dominant inheritance pattern of this disease, we studied the subcellular localization and interaction of wild type and mutant ELOVL4 in COS-7 and HEK 293T cultured cells by immunofluorescence and co-immunoprecipitation. Wild type ELOVL4 containing an endoplasmic reticulum retention sequence was localized to the endoplasmic reticulum as expected. In contrast, disease-associated C-terminal truncation ELOVL4 mutants accumulated as large inclusions exhibiting aggresome-like characteristics in a juxtanuclear position within COS-7 cells. When the wild type and mutant proteins were co-expressed incultured cells, wild type ELOVL4 co-purified with mutant ELOVL4 on an immunoaffinity column and co-localized with the mutant protein in aggresome-like inclusions adjacent to the nucleus. These results indicate that wild type and mutant ELOVL4 form a complex that exhibits an abnormal subcellular localization found for individually expressed mutant ELOVL4. From these studies, we conclude that disease-linked C-terminal truncation mutants of ELOVL4 exert a dominant negative effect on wild type ELOVL4, altering its subcellular localization. This dominant negative mechanism contributes to the autosomal dominant inheritance of Stargardt-like macular dystrophy. Macular degeneration is a heterogeneous group of retinal disorders that represent a major cause of blindness in the developed world. Macular degeneration is characterized by a marked decrease in central vision associated with a loss in visual acuity and degeneration of photoreceptor and retinal pigment epithelial (RPE) 3The abbreviations used are: RPE, retinal pigment epithelial; ER, endoplasmic reticulum; WT, wild type; GFP, green fluorescent protein; PB, phosphate buffer; HEK, human embryonic kidney; TBS, Tris-buffered saline; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.3The abbreviations used are: RPE, retinal pigment epithelial; ER, endoplasmic reticulum; WT, wild type; GFP, green fluorescent protein; PB, phosphate buffer; HEK, human embryonic kidney; TBS, Tris-buffered saline; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. cells in the central retina known as the macula. In a number of cases of macular degeneration, yellow flecks are seen in the fundus resulting from the accumulation of fluorescent lipofuscin deposits in the RPE cells. One such macular degeneration is Stargardt disease (STGD1; OMIM 248200), the most common form of inherited early onset macular degeneration (1Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1077) Google Scholar). This autosomal recessive disorder has been linked to mutations in ABCA4, an ATP-binding cassette transporter implicated in the removal of retinal derivatives from photoreceptor disc membranes (2Weng J. Mata N.L. Azarian S.M. Tzekov R.T. Birch D.G. Travis G.H. Cell. 1999; 98: 13-23Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 3Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 4Beharry S. Zhong M. Molday R.S. J. Biol. Chem. 2004; 279: 53972-53979Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Mutations in this same gene have also been implicated in a number of other retinal degenerative diseases, including retinitis pigmentosa, cone-rod dystrophy, and age-related macular degeneration (5Allikmets R. Shroyer N.F. Singh N. Seddon J.M. Lewis R.A. Bernstein P.S. Peiffer A. Zabriskie N.A. Li Y. Hutchinson A. Dean M. Lupski J.R. Leppert M. Science. 1997; 277: 1805-1807Crossref PubMed Scopus (738) Google Scholar, 6Martinez-Mir A. Paloma E. Allikmets R. Ayuso C. del Rio T. Dean M. Vilageliu L. Gonzalez-Duarte R. Balcells S. Nat. Genet. 1998; 18: 11-12Crossref PubMed Scopus (328) Google Scholar, 7Cremers F.P. van de Pol D.J. van Driel M. den Hollander A.I. van Haren F.J. Knoers N.V. Tijmes N. Bergen A.A. Rohrschneider K. Blankenagel A. Pinckers A.J. Deutman A.F. Hoyng C.B. Hum. Mol. Genet. 1998; 7: 355-362Crossref PubMed Scopus (452) Google Scholar, 8Maugeri A. Klevering B.J. Rohrschneider K. Blankenagel A. Brunner H.G. Deutman A.F. Hoyng C.B. Cremers F.P. Am. J. Hum. Genet. 2000; 67: 960-966Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The gene responsible for two related forms of autosomal dominant macular degeneration known as Stargardt-like macular dystrophy (OMIM 600110) and autosomal dominant macular dystrophy (OMIM 600100) was recently shown to encode a membrane protein known as ELOVL4 for elongation of very long chain fatty acids 4 (9Zhang K. Kniazeva M. Han M. Li W. Yu Z. Yang Z. Li Y. Metzker M.L. Allikmets R. Zack D.J. Kakuk L.E. Lagali P.S. Wong P.W. MacDonald I.M. D.J. R. K. Nat. Genet. PubMed Scopus Google Scholar). The protein of acids of and is expressed in and photoreceptor cells Yang Z. T. W. Yang K. Mol. Google Scholar, R. Wong P.W. R. 2004; PubMed Scopus Google Scholar). was found to with the disease (9Zhang K. Kniazeva M. Han M. Li W. Yu Z. Yang Z. Li Y. Metzker M.L. Allikmets R. Zack D.J. Kakuk L.E. Lagali P.S. Wong P.W. MacDonald I.M. D.J. R. K. Nat. Genet. PubMed Scopus Google and a two by 4 and was found in an in the same P.S. J. Singh N. Hutchinson A. M. Zabriskie N.A. K. K. Leppert M. Allikmets R. Google Scholar). of these mutations cause a resulting in an protein a was a a that results in a protein the C-terminal acids A. Hoyng C.B. C. N. Yang Z. Cremers F.P. K. 2004; PubMed Scopus Google Scholar). The of ELOVL4 is The as to the of ELOVL4 is its with of the ELO gene known to involved in the biosynthesis of very long chain fatty acids S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of this gene family have been studied in are for fatty elongation P. R. S. A. A. B. A. J. Biol. 2000; PubMed Scopus Google Scholar, R. P. L. A. A. P. R. A. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). The of these fatty elongation proteins is with human ELOVL4 containing for of this protein a J. E. PubMed Scopus Google and a endoplasmic reticulum T. J. PubMed Scopus Google Scholar). have been associated with in long chain fatty elongation including J. Y. C. J. P. Hum. Mol. Genet. PubMed Scopus Google and A. H. S. B. S. W. J. S. A.A. Am. J. Hum. Genet. Google Scholar). The of mutations in ELOVL4 fatty biosynthesis in macular for the The in is for and in the have been in retinal degenerative disorders J. Google Scholar, J. B. D.G. Google Scholar, R.T. G.H. P. PubMed Scopus Google Scholar, Birch D.G. Google Scholar, Anderson Anderson 1998; Google Scholar, R.A. 1999; PubMed Google Scholar). is that ELOVL4 involved in the biosynthesis of from H. J. Full Text PDF PubMed Google has been shown to for of the fatty of photoreceptor Anderson PubMed Scopus Google Scholar, 2000; Google Scholar). have that the subcellular localization of wild type ELOVL4 for its of ELOVL4 in has that ELOVL4 is localized to the ER, the of very long chain fatty The effect mutations in ELOVL4 have on the localization of the has One that the mutant proteins resulting from the and were in the R. Lagali P.S. Wong P.W. R. 2004; PubMed Scopus Google in the have that disease-associated ELOVL4 mutants with the are as A. Hoyng C.B. C. N. Yang Z. Cremers F.P. K. 2004; PubMed Scopus Google Scholar, Yang Z. K. Mol. 2004; Google Scholar). is the mechanism of disease in patients with mutations in ELOVL4. To the of ELOVL4 in retinal and in the of autosomal dominant macular degeneration, we have the and localization of and disease-associated mutants of ELOVL4 in a and in retina In this we that ELOVL4 is a membrane that as a ELOVL4 mutants with ELOVL4, resulting in an abnormal localization of ELOVL4 in cells. indicate that ELOVL4 mutants exert a dominant negative effect on ELOVL4, and this mechanism is responsible for the autosomal dominant inheritance pattern of Stargardt-like macular dystrophy. of ELOVL4 ELOVL4 was from human retinal by the were The was the and of the and the of the in with the of were to the of ELOVL4 in the a and a The ELOVL4 mutants and and were a the the ELOVL4 in and in as of the were by of ELOVL4 C-terminal acids of human ELOVL4 were in with the of in the were with protein that been on were as D. Molday R.S. J. Biol. Chem. Full Text PDF PubMed Google and for to ELOVL4 of The of were the The to the acids the C-terminal acids of ELOVL4 were to a and was by of retina was for immunofluorescence as D. Molday R.S. Google Scholar). The were and for in phosphate containing and and with in containing were also with a for by were with containing and for with and in were with the retinal were a and 293T and COS-7 cells were in with HEK 293T cells were in with of phosphate C. H. Mol. Cell. Biol. 7: PubMed Scopus Google and of and of were and to of was with of the ELOVL4 to that the were of 293T and COS-7 cells were on and The and were in a cells were in and for in for in in were and for in containing and and with for in The M. Molday Molday R.S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google was and and the of the were used a The were also and and and with were in for was a of ELOVL4 was to as M. Molday Molday R.S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). 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Hoyng C.B. C. N. Yang Z. Cremers F.P. K. 2004; PubMed Scopus Google Scholar, R. Lagali P.S. Wong P.W. R. 2004; PubMed Scopus Google Scholar, Yang Z. K. Mol. 2004; Google to the of the retention the of the mutant protein has been One group that the mutant is to the R. Lagali P.S. Wong P.W. R. 2004; PubMed Scopus Google that is in the as large inclusions A. Hoyng C.B. C. N. Yang Z. Cremers F.P. K. 2004; PubMed Scopus Google Scholar, Yang Z. K. Mol. 2004; Google Scholar). have the localization of the identified disease-linked in COS-7 and HEK 293T cells with an In to the localization of the protein and the mutant was in a juxtanuclear position and in the of cells, of its within an within the To the mutant and were with and The protein localization with the protein a of with a protein involved in membrane the and and membranes of the J. Biol. 2000; PubMed Scopus Google Scholar). This also represent a of in this localization. The mutant protein with and and the that the of the been in these cells. In cells of the mutant protein was the on the mutant protein in the for L. A. Nat. Mol. Cell. Biol. PubMed Scopus Google Scholar). ELOVL4 to with known as J. Biol. 1998; PubMed Scopus Google Scholar, Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. J. PubMed Google Scholar). One of the most common of in is the of the proteins and a major of with in COS-7 HEK 293T cells In cells with the were and to form a that co-localized with the mutant ELOVL4. This of has been in aggresome-like J. Biol. 1998; PubMed Scopus Google Scholar, R.S. J. PubMed Google Scholar, R. Z. J. Biol. 1999; PubMed Scopus Google Scholar, R.S. N.F. J. Biol. Chem. 277: Full Text Full Text PDF PubMed Scopus Google and that mutant ELOVL4 form aggresome-like inclusions in the of and ELOVL4 to and disease-linked ELOVL4 mutants to form a complex co-expressed in cultured cells. To determine whether mutant ELOVL4 the localization of ELOVL4, we the of and mutant ELOVL4 in COS-7 cells. When and were proteins localized to the with the of ELOVL4. was with the the protein accumulated with the mutant as inclusions in a juxtanuclear position in cells In the also the of the protein to and the protein to inclusions To that the of the and mutant proteins was by the of the large of the we also the of and used an of the two to the of ELOVL4 in patients with autosomal dominant macular degeneration. When the two were co-expressed in COS-7 cells, proteins co-localized in the pattern was co-expressed with proteins were in the juxtanuclear The same was in cells with and the mutant ELOVL4 in COS-7 HEK 293T cells These indicate that the interaction of mutant ELOVL4 with ELOVL4 the subcellular localization of the C-terminal truncation mutations in ELOVL4 have been identified in patients with an autosomal dominant form of macular degeneration known as Stargardt-like macular the mechanism this retinal disease is The dominant disease in from a of of the mutant a dominant negative effect of the mutant on the as in the of mutations in linked to autosomal dominant forms of retinitis and macular dystrophy W. S. Birch D. D. Travis G.H. S. A. 98: PubMed Scopus Google Scholar, Molday R.S. Mol. Biol. Cell. PubMed Scopus Google Scholar). To this we have studied the and subcellular localization and interaction of and disease-associated ELOVL4 by immunofluorescence and developed and The localization of ELOVL4 and in retina R. Wong P.W. R. 2004; PubMed Scopus Google and in Yang Z. T. W. Yang K. Mol. Google that ELOVL4 is expressed in cells of embryonic and retina and to in In of human retina and retina from other ELOVL4 is found within the of and R. Lagali P.S. Wong P.W. R. 2004; PubMed Scopus Google Scholar, P.S. J. R. Kakuk L.E. Bernstein Wong P.W. R. PubMed Scopus Google Scholar). we have that ELOVL4 is expressed in of the retina also in and photoreceptor cells of the macular and of the the of the retina associated with autosomal dominant Stargardt-like disease A. T. T. Full Text Full Text PDF PubMed Scopus Google Scholar, C. R. Mol. Google Scholar). The most was found in the of the the to the also of the the a has been of in patients with autosomal dominant macular dystrophy to the of ELOVL4 in cells of retina is on the of ELO family from In this we have used and to that ELOVL4 a its This is for protein the mutant is expressed the to the also the of ELOVL4 by with expressed ELOVL4 ELOVL4 proteins co-purified on immunoaffinity co-expressed in HEK 293T cells, that ELOVL4 forms a The ELOVL4 mutant also co-purified with ELOVL4, that the of ELOVL4 is for the of ELOVL4 by and found that the complex of ELOVL4 and expressed ELOVL4 as heterogeneous of the to protein these proteins are To is on the of and the of these to that ELOVL4 as a heterogeneous complex is in with on that these are also heterogeneous as by R. C. PubMed Scopus Google Scholar, E. R. C. PubMed Scopus Google Scholar, S. A. C. R. 2000; PubMed Scopus Google Scholar). are to determine whether the ELOVL4 by and are in the elongation of very long chain fatty acids. The of for the of ELOVL4 as a in the biosynthesis of very long chain fatty acids. we have shown that disease-associated ELOVL4 mutants with ELOVL4 by co-immunoprecipitation. a of this ELOVL4 localized to the was by the mutant ELOVL4 to inclusions in a juxtanuclear position within the the same subcellular localization for individually expressed ELOVL4 the mutant ELOVL4 its interaction with ELOVL4 a dominant negative effect on the of ELOVL4, to to in cells. The localization of ELOVL4 is for its in the elongation of very long chain fatty the has been identified as the of very long chain fatty biosynthesis L. PubMed Scopus Google Scholar). has been on the subcellular localization of individually expressed disease-linked ELOVL4 the retention One that mutant ELOVL4 is in the R. Lagali P.S. Wong P.W. R. 2004; PubMed Scopus Google Scholar). have shown of mutant ELOVL4 with the of of mutant ELOVL4 within the A. Hoyng C.B. C. N. Yang Z. Cremers F.P. K. 2004; PubMed Scopus Google Scholar, Yang Z. K. Mol. 2004; Google Scholar). results are with the found that the mutant ELOVL4 with for the and the mutant protein to the has been for proteins in the known as J. Biol. 1998; PubMed Scopus Google Scholar, R.S. J. PubMed Google Scholar). with these studies, we also found that mutant ELOVL4 a in the of that ELOVL4 in the form aggresome-like by the of the accumulated mutant have been in patients mutations in ELOVL4, that is for the of ELOVL4 protein that ELOVL4 is for early of The mechanism the of the disease in is to inclusions have been in of retinitis R.S. J. PubMed Google Scholar, R.S. N.F. J. Biol. Chem. 277: Full Text Full Text PDF PubMed Scopus Google have been in in human patients of retinitis One that are very the of mutant protein to cultured cells and cause the to the accumulated protein Yang Z. K. Mol. 2004; Google have an of in cells mutant ELOVL4 with a mechanism in is The of ELOVL4 to and the of Stargardt-like macular dystrophy to the of ELOVL4 gene in the ELO family is to encode a of complex that in the elongation of long chain fatty acids L. PubMed Scopus Google Scholar). ELOVL4 involved in the involved in the of ELOVL4 in in the has to The removal of mutant ELOVL4 by photoreceptor to the removal of ELOVL4, the of ELOVL4 in the ER, the complex containing mutant and ELOVL4 are the for very long chain fatty acids in by ELOVL4 the to The of ELOVL4 to the of by the accumulation of its by a of its fatty This in to the of other proteins F.J. L.E. J. PubMed Scopus Google Scholar, M. A.A. 2000; PubMed Scopus Google Scholar, J. Wong Molday R.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google to photoreceptor degeneration. The of patients with autosomal dominant Stargardt-like disease is to the of patients with autosomal recessive Stargardt disease including the of yellow flecks in the central retina the of the RPE cells and of the central and RPE cells. is a member of the ATP-binding cassette family of proteins (1Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1077) Google Scholar, M. Molday Molday R.S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). has been to in the removal of from disc membranes the of (2Weng J. Mata N.L. Azarian S.M. Tzekov R.T. Birch D.G. Travis G.H. Cell. 1999; 98: 13-23Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 3Sun H. Molday R.S. Nathans J. J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 4Beharry S. Zhong M. Molday R.S. J. Biol. Chem. 2004; 279: 53972-53979Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). decrease in to an accumulation of in disc membranes and the of including derivatives that as fluorescent lipofuscin deposits in RPE cells as a of of The of has been shown to on the J. Wong Molday R.S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is that loss in ELOVL4 in patients with autosomal dominant Stargardt-like disease the of in disc to the of lipofuscin deposits in the RPE as found in with autosomal recessive Stargardt disease and (2Weng J. Mata N.L. Azarian S.M. Tzekov R.T. Birch D.G. Travis G.H. Cell. 1999; 98: 13-23Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar). the in ELOVL4 have been C. Yang Z. D.J. Y. S. Li C. Birch D.G. K. S. A. PubMed Scopus Google Scholar). These an accumulation of lipofuscin containing and its in the RPE cells. the mutant ELOVL4 photoreceptor degeneration that was related to the of the mutant with the of disease in with These are with the of this that the mutant ELOVL4 a dominant negative The that mutant ELOVL4 photoreceptor degeneration that the dominant negative effect of the mutant protein on ELOVL4 other photoreceptor This is the to that mutant ELOVL4 with ELOVL4, and this interaction to of the protein to within cells. major is to C-terminal truncation of ELOVL4 protein and to autosomal dominant Stargardt-like macular dystrophy. for in the of the ELOVL4 and Molday for

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