Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease
| Autor: | Andrea L. Webber, Nawajes A. Mandal, Norman Salem, Konstantin Petrukhin, Vidyullatha Vasireddy, Radha Ayyagari, Sharon Majchrzak, Paul A. Sieving, Dorit Raz-Prag, Ronald A. Bush, Robert N. Fariss |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Rhodopsin Protein family Genotype Blotting Western Biology Retina Article Lipofuscin Frameshift mutation Macular Degeneration Mice Electroretinography Animals RNA Messenger Eye Proteins chemistry.chemical_classification Mice Knockout Reverse Transcriptase Polymerase Chain Reaction Fatty Acids Fatty acid Membrane Proteins Amino acid Cell biology Mice Inbred C57BL Disease Models Animal Biochemistry chemistry Gene Expression Regulation Haplotypes Docosahexaenoic acid Female Haploinsufficiency Gene Deletion Polyunsaturated fatty acid |
| Zdroj: | Investigative ophthalmologyvisual science. 47(8) |
| ISSN: | 0146-0404 |
| Popis: | Human macular degeneration is generally characterized by a gradual deterioration in central vision accompanied by structural pathologic conditions such as atrophy of the retinal pigment epithelium (RPE), accumulation of lipofuscin in the RPE, and regional loss of photoreceptors.1,2 Stargardt disease 3 (STGD3) is an early-onset autosomal dominant form of atrophic macular degeneration that results from a 5-bp deletion mutation, and possibly other mutations, in the ELOVL4 gene (elongation of very-long-chain fatty acids [LCFAs]), which maps to 6q14.3–6 The deletion causes a frameshift and loss of a 51-amino-acid fragment at the C terminus including a dilysine (KXKXX) targeting signal, creating a premature stop codon and leading to synthesis of an aberrant ELOVL4 peptide.5 The wild-type ELOVL4 protein is found in the endoplasmic reticulum (ER), which is the site of very-LCFA biosynthesis.7 However, the intracellular trafficking of the truncated form is defective and appears to be sequestered in aggresomes in a complex that also includes mislocalized wild-type ELOVL4.5–14 The importance of ELOVL4 protein is implied by its evolutionary conservation. Human ELOVL4 encodes a protein of 314 amino acids with approximately 35% amino acid identity to members of the ELO protein family in yeast,5 and orthologues have been identified in other species, including Caenorhabditis elegans, zebrafish, and chicken.15–18 The cellular function of ELOVL4 is unknown, but homology with yeast proteins suggests that it is an ER-bound transmembrane protein associated with LCFA synthesis.5 LC polyunsaturated fatty acids (PUFAs) from the n-6 and n-3 classes are essential for brain and retinal development and for visual function.19 An important role for docosahexaenoic acid (DHA) within the retina is suggested by its high levels and active conservation in this tissue.5,20,21 ELOVL4 is expressed in rod and cone photoreceptor cells and is probably involved in one of the elongation steps necessary for fatty acid biosynthesis.5,20–23 The essential role of ELOVL4 in polyunsaturated fatty acids (PUFA) synthesis is also suggested by preliminary evidence of improved visual function in human STGD3 disease with supplementation of DHA.24 Another recent study found that phenotypic severity in a family with STGD3 disease correlates with dietary fatty acid intake, and that a high dietary intake of DHA may partially ameliorate the maculopathy.25 We characterized heterozygous animals in a mouse model with a targeted deletion of Elovl4, to further understand the role of this gene in macular degeneration. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|