ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function. (March 2019)

• Record Type: Journal Article
• Authors: Hopiavuori, Blake R.; Anderson, Robert E.; Agbaga, Martin-Paul
• Is Part Of: Progress in retinal and eye research. Volume 69(2019:Mar.)
• Page Start: 137
• Page End: 158
• Publication Date: 2019-03
• Subjects: Stargardt -- ELOVL4 -- Spinocerebellar ataxia -- Very long-chain fatty acids -- VLC-PUFA -- VLC-SFA; Retina -- Periodicals; Retina -- Research -- Methodology -- Periodicals; Eye -- Diseases -- Periodicals; Eye -- Periodicals; Eye Diseases -- Periodicals; Retina -- Periodicals; Rétine -- Périodiques; Rétine -- Recherche -- Méthodologie -- Périodiques; 617.7005
• DOI: 10.1016/j.preteyeres.2018.10.004
• Languages: English
• ISSNs: 1350-9462

Abstract

Abstract: ELO ngation ofV eryL ong chain fatty acids-4 ( ELOVL4) is an elongase responsible for the biosynthesis of very long chain (VLC, ≥C28) saturated (VLC-SFA) and polyunsaturated (VLC-PUFA) fatty acids in brain, retina, skin, Meibomian glands, and testes. Fascinatingly, different mutations in this gene have been reported to cause vastly different phenotypes in humans. Heterozygous inheritance of seven different mutations in the coding sequence and 5' untranslated region of ELOVL4 causes autosomal dominant Stargardt-like macular dystrophy (STGD3), while homozygous inheritance of three more mutant variants causes severe seizures with ichthyosis, hypertonia, and even death. Some recent studies have described heterozygous inheritance in yet another three mutant ELOVL4 variants, two that cause spinocerebellar ataxia-34 (SCA34) with erythrokeratodermia (EKV) and one that causes SCA34 without EKV. We identified the specific enzymatic reactions catalyzed by ELOVL4 and, using a variety of genetically engineered mouse models, have actively searched for the mechanisms by which ELOVL4 impacts neural function and health. In this review, we critically compare and contrast the various animal model and case studies involving ELOVL4 deficiency via either mutation or deletion, and the resulting consequences on neuronal health and function in both the retina and central nervous system. Highlights: Different mutations in ELOVL4 cause vastly different phenotypes in humans. Loss of very long-chain fatty acids causes retinal dysfunction in Stargardt disease. Very long-chain fatty acids impose unique biophysical influences on cell membranes. Fatty acids influence cell function based on length and degree of unsaturation. Mutant ELOVL4 causes RPE toxicity in Stargardt disease.