Disease relevance of ELOVL4

• Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration [1].

High impact information on ELOVL4

• A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy [2].
• Here we limit the minimum genetic region for STGD3 and adMD to a 0.6-cM interval by recombination breakpoint mapping and identify a single 5-bp deletion within the protein-coding region of a new retinal photoreceptor-specific gene, ELOVL4, in all affected members of STGD3 and adMD families [2].
• We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD [1].
• Mutations in elongation of very long-chain fatty acid-4 (ELOVL4) are associated with autosomal dominant Stargardt-like macular degeneration (STGD3), with a five base-pair (5 bp) deletion mutation resulting in the loss of 51 carboxy-terminal amino acids and truncation of the protein [3].
• PLEKHA1, which is closely linked to LOC387715, was significantly associated with ARM status in the AREDS cohort, but not the CHS cohort and ELOVL4 was not significantly associated with ARM in either cohort [4].

Biological context of ELOVL4

• No mutation was found in the exons of three candidate genes, but we obtained three non-pathogenic polymorphisms, IVS5-2533T-->A in ELOVL4, 558C-->T (Val106Val) and 1150G-->C (Glu304Gln) in RDS [5].
• 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 [6].
• The only coding DNA sequence variant identified in these four genes was a 5-bp deletion in exon 6 of ELOVL4 [7].
• Evolutionarily conserved ELOVL4 gene expression in the vertebrate retina [8].
• To study cellular status of cells expressing mutant ELOVL4 proteins, transfected cells were examined for upregulation of Bip and CHOP, markers for the unfolded protein response (UPR) by western blotting [9].

Anatomical context of ELOVL4

• Wild type ELOVL4 containing an endoplasmic reticulum retention sequence was localized to the endoplasmic reticulum as expected [6].
• 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 [6].
• We expressed the wild-type and mutant proteins in COS-7 and CHO cells to study the intracellular distribution of ELOVL4 and to identify possible implications of the above mutations in its localization [10].
• Immunofluorescence analysis of these proteins along with organelle marker antibodies revealed predominant ER localization for wild-type ELOVL4 [10].
• Association of adipose and red blood cell lipids with severity of dominant Stargardt macular dystrophy (STGD3) secondary to an ELOVL4 mutation [11].

Associations of ELOVL4 with chemical compounds

• ELOVL4 protein aggregates were measured by co-immunoprecipitation and by sucrose gradient centrifugation followed by immunodetection with western blots [9].

Physical interactions of ELOVL4

• Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene [12].

Other interactions of ELOVL4

• EST and HTGS databases were searched for orthologs of ELOVL4 [13].
• Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus [14].
• However, as the autosomal dominant Stargardt-like macular dystrophies are genetically heterogeneous, other forms of this disorder, in particular STGD3 previously linked to 6q, may be caused by mutations in IMPG1 [15].
• APOE and ELOVL4 genotypes do not seem to modify risk [16].
• Cigarette Smoking, CFH, APOE, ELOVL4, and Risk of Neovascular Age-Related Macular Degeneration [16].

Analytical, diagnostic and therapeutic context of ELOVL4

• RESULTS: The existence of ELOVL4 sequence orthologues and homologues was confirmed by both Southern blot analysis and in silico searches of protein sequence databases [8].
• Northern blot analysis revealed the presence of multiple transcripts corresponding to ELOVL4 homologues expressed in the retina of several different mammalian species [8].
• METHODS: Bovine and porcine orthologs of the human ELOVL4 gene were cloned using RT-PCR method [13].
• The combination of denaturing high-performance liquid chromatography (DHPLC) analysis and direct sequencing of all available family members was used to further assess segregation of identified ELOVL4 variants in the pedigree [12].
• Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability [17].

References