A New<i>ELOVL4</i>Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia

Bourassa, Cynthia V.; Raskin, Salmo; Serafini, Sérgio Zuñeda; Teive, Hélio A.G.; Dion, Patrick A.; Rouleau, Guy A.

doi:10.1001/jamaneurol.2015.0888

Cited by 36 publications

(55 citation statements)

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“…Inheritance of mutant ELOVL4 alleles has important consequences in the CNS that depend on the specific mutation inherited and whether inheritance is heterozygous or homozygous, indicating that VLC-FAs are critical to normal health and brain function (Bernstein et al, 2001; Edwards et al, 2001; Zhang et al, 2001; Aldahmesh et al, 2011; Cadieux-Dion et al, 2014; Mir et al, 2014; Bourassa et al, 2015; Ozaki et al, 2015; Agbaga, 2016). The relationship of ELOVL4 mutations, inheritance patterns, and symptoms in human disease is complex, and the precise mechanisms underlying the presentation of each disease are unclear (Agbaga, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…The striking down-regulation of ELOVL4 in the basal ganglia suggests that these regions of the brain are not likely to be the underlying cause of the neural dysfunction in diseases arising from mutant forms of ELOVL4 . The slower neurodegenerative changes that characterize disease arising from heterozygous inheritance of mutant ELOVL4 alleles in STDG3 (Bernstein et al, 2001; Edwards et al, 2001; Zhang et al, 2001) and SCA-34 (Cadieux-Dion et al, 2014; Bourassa et al, 2015; Ozaki et al, 2015) may reflect slow compromise of neural function due to the presence of a single dysfunctional ELOVL4 allele. However, a particularly intriguing question is why one set of ELOVL4 mutations would lead to a retinal degeneration with no other problems in the brain, while a different set of ELOVL4 mutations would cause spinocerebellar ataxia without any retinal involvement.…”

Section: Discussionmentioning

confidence: 99%

“…To date, nine different mutations in the human ELOVL4 gene have been identified that cause neurological disorders (Bernstein et al, 2001; Edwards et al, 2001; Zhang et al, 2001; Aldahmesh et al, 2011; Cadieux-Dion et al, 2014; Mir et al, 2014; Bourassa et al, 2015; Ozaki et al, 2015; Agbaga, 2016). Homozygous mutations in human ELOVL4 cause neurological disorders characterized by seizures, intellectual disability, and neurodegenerative disease (Aldahmesh et al, 2011; Mir et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Homozygous mutations in human ELOVL4 cause neurological disorders characterized by seizures, intellectual disability, and neurodegenerative disease (Aldahmesh et al, 2011; Mir et al, 2014). Several heterozygous mutations in human ELOVL4 have been identified that cause autosomal dominant spinocerebellar ataxia (type 34; SCA34) and/or erythrokeratodermia variabilis (EKV) with no significant retinal phenotype (Cadieux-Dion et al, 2014; Bourassa et al, 2015; Ozaki et al, 2015). Other heterozygous ELOVL4 mutations cause autosomal dominant Stargardt-like macular dystrophy (STGD3) without any skin or CNS phenotype (Bernstein et al, 2001; Edwards et al, 2001; Zhang et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Distribution of ELOVL4 in the Developing and Adult Mouse Brain

et al. 2017

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ELOngation of Very Long chain fatty acids (ELOVL)-4 is essential for the synthesis of very long chain-fatty acids (fatty acids with chain lengths ≥ 28 carbons). The functions of ELOVL4 and its very long-chain fatty acid products are poorly understood at present. However, mutations in ELOVL4 cause neurodevelopmental or neurodegenerative diseases that vary according to the mutation and inheritance pattern. Heterozygous inheritance of different ELOVL4 mutations causes Stargardt-like Macular Dystrophy or Spinocerebellar Ataxia type 34. Homozygous inheritance of ELOVL4 mutations causes more severe disease characterized by seizures, intellectual disability, ichthyosis, and premature death. To better understand ELOVL4 and very long chain fatty acid function in the brain, we examined ELOVL4 expression in the mouse brain between embryonic day 18 and postnatal day 60 by immunolabeling using ELOVL4 and other marker antibodies. ELOVL4 was widely expressed in a region-and cell type-specific manner, and was restricted to cell bodies, consistent with its known localization to endoplasmic reticulum. ELOVL4 labeling was most prominent in gray matter, although labeling also was present in some cells located in white matter. ELOVL4 was widely expressed in the developing brain by embryonic day 18 and was especially pronounced in regions underlying the lateral ventricles and other neurogenic regions. The basal ganglia in particular showed intense ELOVL4 labeling at this stage. In the postnatal brain, cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, midbrain, pons, and medulla all showed prominent ELOVL4 labeling, although ELOVL4 distribution was not uniform across all cells or subnuclei within these regions. In contrast, the basal ganglia showed little ELOVL4 labeling in the postnatal brain. Double labeling studies showed that ELOVL4 was primarily expressed by neurons, although presumptive oligodendrocytes located in white matter tracts also showed labeling. Little or no ELOVL4 labeling was present in astrocytes or radial glial cells. These findings suggest that ELOVL4 and its Sherry et al. ELOVL4 Distribution in the Brain very long chain fatty acid products are important in many parts of the brain and that they are particularly associated with neuronal function. Specific roles for ELOVL4 and its products in oligodendrocytes and myelin and in cellular proliferation, especially during development, are possible.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distribution of ELOVL4 in the Developing and Adult Mouse Brain

et al. 2017

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“…Also, recent studies have linked spinocerebellar ataxia to ELOVL4 mutations 30–32 . Moreover, recessive mutations in ELOVL4 result in impaired neural development, neuronal dysfunction, hyper-excitability and seizures 28, 33 , and neuroichthyotic disorders 34 .…”

Section: Introductionmentioning

confidence: 99%

Elovanoids are novel cell-specific lipid mediators necessary for neuroprotective signaling for photoreceptor cell integrity

Jun

Mukherjee

Asatryan

et al. 2017

Sci Rep

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Docosahexaenoic acid (DHA, 22:6 n-3) is abundant in the retina and is enzymatically converted into pro-homeostatic docosanoids. The DHA- or eicosapentaenoic acid (EPA)-derived 26 carbon fatty acid is a substrate of elongase ELOVL4, which is expressed in photoreceptor cells and generates very long chain (≥C28) polyunsaturated fatty acids including n-3 (VLC-PUFAs,n-3). While ELOVL4 mutations are linked to vision loss and neuronal dysfunctions, the roles of VLC-PUFAs remain unknown. Here we report a novel class of lipid mediators biosynthesized in human retinal pigment epithelial (RPE) cells that are oxygenated derivatives of VLC-PUFAs,n-3; we termed these mediators elovanoids (ELV). ELVs have structures reminiscent of docosanoids but with different physicochemical properties and alternatively-regulated biosynthetic pathways. The structures, stereochemistry, and bioactivity of ELVs were determined using synthetic materials produced by stereo-controlled chemical synthesis. ELVs enhance expression of pro-survival proteins in cells undergoing uncompensated oxidative stress. Our findings unveil a novel autocrine/paracrine pro-homeostatic RPE cell signaling that aims to sustain photoreceptor cell integrity and reveal potential therapeutic targets for retinal degenerations.

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ELOVL4 with erythrokeratoderma: A pediatric case and emerging genodermatosis

Croitoru

Lara‐Corrales

et al. 2021

American J of Med Genetics Pt A

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A NewELOVL4Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia

Cited by 36 publications

References 7 publications

Distribution of ELOVL4 in the Developing and Adult Mouse Brain

Distribution of ELOVL4 in the Developing and Adult Mouse Brain

Elovanoids are novel cell-specific lipid mediators necessary for neuroprotective signaling for photoreceptor cell integrity

ELOVL4 with erythrokeratoderma: A pediatric case and emerging genodermatosis

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