A Novel Mutation in the<i>ELOVL4</i>Gene Causes Autosomal Dominant Stargardt-like Macular Dystrophy

Maugeri, Alessandra; Meire, Françoise; Hoyng, Carel B.; Vink, Carolien; Regemorter, N. Van; Karan, Goutam; Yang, Zhenglin; Cremers, Frans P.M.; Zhang, Keqing

doi:10.1167/iovs.04-0078

Cited by 81 publications

(63 citation statements)

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“…Stargardt disease | condensing enzyme | photoreceptor degeneration T hree independent mutations in the last exon (exon 6) of the elongation of very-long-chain fatty acids-like 4 (ELOVL4) gene cause the pathogenesis of autosomal-dominant Stargardtlike juvenile macular dystrophy [Stargardt3 (STGD3)], resulting in loss of central vision with progressive degeneration of the macula and peripheral retina in humans (1)(2)(3)(4). A recent study reported severe skin and brain dysfunction in patients with homozygous mutations in ELOVL4 (5).…”

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“…A recent study reported severe skin and brain dysfunction in patients with homozygous mutations in ELOVL4 (5). The resultant frameshift leads to premature termination of the encoded protein, loss of its C-terminal endoplasmic reticulum (ER) retention signal, and subsequent protein mislocalization and aggregation in cultured cells (4,(6)(7)(8). In 2008, ELOVL4 was shown to be involved in the elongation of C26 to C28 very-long-chain (VLC) fatty acids, saturated (FA) and polyunsaturated (PUFA) (9).…”

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Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.Stargardt disease | condensing enzyme | photoreceptor degeneration

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Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Three alleles have been identified as the cause for STGD3, each possessing a mutation in the last exon (exon 6) of ELOVL4. These mutations include a 5-bp deletion (790 -794delAACTT), two 1-bp deletions (789delT and 794delT), and a single transversion (C-to-G at position 810) resulting in a premature stop codon (Y270X) (4,10,11). Each ELOVL4 mutation results in a truncated protein with a carboxyl-terminal dilysine motif absent, leading to loss of retention in the ER; very long chain polyunsaturated fatty acid (VLC-PUFA) biosynthesis takes place in the ER (12).…”

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Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function

Harkewicz

Tong

et al. 2012

Journal of Biological Chemistry

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Background: Phospholipids containing very long chain polyunsaturated fatty acids (VLC-PUFAs) are enriched in retina. Results: Specific ELOVL4 rod or cone photoreceptor conditional knock-outs cause decreases in retinal VLC-PUFAs. Conclusion: ELOVL4 is critical for the synthesis of phosphatidylcholine-containing sn-1 VLC-PUFAs and vision. Significance: ELOVL4 mutations are implicated in Stargardt disease, a type of juvenile macular degeneration.

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“…Both the 5-bp deletion and the two 1-bp deletions are predicted to result in a similar truncated ELOVL4 protein. A third mutation in ELOVL4, 270stop, which should also generate a truncated ELOVL4 protein, has been identified recently in a Dutch family with dominant STGD (10). The importance of the function of ELOVL4 in the synthesis of polyunsaturated fatty acids is emphasized by the observation that the severity of STDG3 can be alleviated by dietary supplements of EPA and DHA (11,12).…”

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Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration

Karan

Lillo

Yang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.phagosome ͉ Stargardt disease ͉ photoreceptor ͉ retinal pigment epithelium M acular degeneration involves the death of photoreceptor cells in the central retina, which is responsible for fine-detail vision. Age-related macular degeneration (AMD) affects Ϸ30% of people over the age of 75 (1, 2), and is becoming a greater health problem with the rapidly growing elderly population of developed countries. There is no treatment to halt or reverse the disease for the dry form, which comprises Ϸ90% of AMD cases. Moreover, there is a lack of suitable animal models for experimentation on therapies for dry AMD. Stargardt macular dystrophy (STGD) shares pathological features with AMD, except that it occurs at a young age. Both AMD and STGD are characterized by the accumulation of high levels of lipofuscin in the retinal pigment epithelium (RPE), which precedes degeneration of the photoreceptors in the macula and RPE atrophy.The gene responsible for an autosomal dominant form of STGD, STDG3, was identified recently as ELOVL4 (3, 4). It is predicted to encode an enzyme involved in the elongation of very long-chain fatty acids (hence the name, ELOVL), and is highly expressed in rod and cone photoreceptor cells (5, 6). Sequence analysis of human ELOVL4 cDNA predicts a protein of 314 aa that shares homology with members of the yeast Elo (elongation of long chain fatty acid) family and the human ELO1 homolog (HELO1) (3). HELO1 and the ELO family members possess biochemical features that suggest their participation in reduction reactions occurring during fatty acid elongation (7,8). Mutational analysis of the ELOVL4 gene in five large STGD-like macular dystrophy pedigrees revealed a 5-bp deletion, resulting in a frame-shift and the introduction of a stop codon, 51 codons from the end of the coding region (3). Subsequently, two 1-bp deletions, 789delT and 794delT, in ELOVL4 were identifi...

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A Novel Mutation in theELOVL4Gene Causes Autosomal Dominant Stargardt-like Macular Dystrophy

Cited by 81 publications

References 14 publications

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration

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