Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis:  Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization

Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) is a fatty acid elongase responsible for very long-chain fatty acid biosynthesis in the brain, retina, and skin. Heterozygous mutations in ELOVL4 gene cause Stargardt-like macular dystrophy and spinocerebellar ataxia type-34, while different homozygous mutations have been associated with ichthyosis, spastic quadriplegia, and mental retardation syndrome in three kindred. We report the first two Italian children affected with neuro-ichthyosis due to the previously undescribed ELOVL4 homozygous frameshift variant c.435dupT (p.Ile146TyrfsTer29), and compound heterozygous variants c.208C>T (p.Arg70Ter) and c.487T>C (p.Cys163Arg), respectively. Both patients were born with collodion membrane followed by development of diffuse mild hyperkeratosis and scaling, localized erythema, and palmoplantar keratoderma. One infant displayed mild facial dysmorphism. They suffered from failure to thrive, and severe gastro-esophageal reflux with pulmonary aspiration. The patients presented axial hypotonia, hypertonia of limbs, and absent head control with poor eye contact from infancy. Visual evoked potentials showed markedly increased latency and poor morphological definition, indicative of alteration of the retro-retinal visual pathways in both patients. Ultrastructural skin examination revealed abnormalities of lamellar bodies with altered release in the epidermal granular and horny layer intracellular spaces. Our findings contribute to expanding the phenotypic and genotypic features of ELOVL4-related neuro-ichthyosis.

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Enhanced expression of avfae1 encoding a long-chain fatty acid elongase during the induction of the antifungal diene in avocado fruits

Physiological and Molecular Plant Pathology ◽

10.1016/j.pmpp.2005.01.004 ◽

2004 ◽

Vol 65 (4) ◽

pp. 171-180 ◽

Cited By ~ 6

Author(s):

X. Wang ◽

I. Kobiler ◽

A. Lichter ◽

A. Leikin-Frenkel ◽

D. Prusky

Keyword(s):

Fatty Acid ◽

Chain Fatty Acid ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase ◽

Enhanced Expression ◽

Long Chain

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Identification of a Long-Chain Fatty Acid Elongase from Nannochloropsis sp. Involved in the Biosynthesis of Fatty Acids by Heterologous Expression in Saccharomyces cerevisiae

Journal of Ocean University of China ◽

10.1007/s11802-019-3946-y ◽

2019 ◽

Vol 18 (5) ◽

pp. 1199-1206 ◽

Cited By ~ 2

Author(s):

Minrui Guo ◽

Guogang Chen ◽

Jiluan Chen ◽

Minggang Zheng

Keyword(s):

Saccharomyces Cerevisiae ◽

Fatty Acids ◽

Fatty Acid ◽

Heterologous Expression ◽

Chain Fatty Acid ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase ◽

Long Chain

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Quantitative Structure Activity Relationship Studies on a Novel Indolediones as Long Chain Fatty Acid Elongase 6 (ELOVL6) Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/157018011795514168 ◽

2011 ◽

Vol 8 (5) ◽

pp. 422-429 ◽

Cited By ~ 2

Author(s):

Junxia Zheng ◽

Zhiwei Wu ◽

Mibei Dai ◽

Zhihui Xu ◽

Xiaomei Li ◽

...

Keyword(s):

Fatty Acid ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Chain Fatty Acid ◽

Activity Relationship ◽

Quantitative Structure ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase ◽

Structure Activity ◽

Long Chain

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High-Fat Diet Elevates Liver Docosahexaenoic Acid Possibly through Over-Expression of Very Long-Chain Fatty Acid Elongase 2 in C57BL/6J Mice

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000432 ◽

2019 ◽

Vol 89 (1-2) ◽

pp. 62-72

Author(s):

Mooli Raja Gopal Reddy ◽

Gundluri Venkata Asha ◽

Sravan Kumar Manchiryala ◽

Uday Kumar Putcha ◽

Ayyalasomayajula Vajreswari ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

High Fat Diet ◽

Chain Fatty Acid ◽

High Fat ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase ◽

Over Expression ◽

Long Chain

Abstract. The liver is the main site of lipid metabolism and vitamin A storage. Dietary factors are known to affect liver function, thereby leading to metabolic abnormalities. Here, we assessed the impact of long-term feeding of a high-fat diet on hepatic vitamin A status and lipid metabolism. For this purpose, 14 male and 14 female 35-day-old mice (strain C57BL/6J) were each divided into 2 groups of 7 animals and fed either a stock diet or a high-fat (HF) diet for 26 weeks. In addition to increased body weight/weight gain, the HF diet induced hypertriglyceridemia in both (p < 0.01). However, liver triglyceride levels were comparable among groups, which could be partly explained by unaltered expression of various lipogenic pathway proteins such as sterol regulatory element binding protein 1 (SREBP1), fatty acid synthase (FAS), microsomal triglyceride transfer protein (MTTP), and glycerol 3-phosphate acyl transferase (GPAT). On the other hand, hepatic retinol stores increased significantly in both sexes, whereas males displayed elevated circulatory retinol levels. Notably, long-term feeding of a HF diet elevated n-3 polyunsaturated fatty acid (PUFA) and docosahexaenoic acid (DHA, C22:6) levels in the liver (p ≤ 0.001), which is in line with the over-expression of very long-chain fatty acid elongase 2 (ELOVL2) protein in both sexes of mice (p < 0.01). In conclusion, very long-term feeding of a HF diet increased hepatic retinol stores and induced hypertriglyceridemia. However, it had no effect on hepatic triglyceride accumulation, possibly due to increased DHA levels arising from the ELOVL2-mediated elongation pathway.

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A Specific Structural Requirement for Ergosterol in Long-chain Fatty Acid Synthesis Mutants Important for Maintaining Raft Domains in Yeast

Molecular Biology of the Cell ◽

10.1091/mbc.e02-02-0116 ◽

2002 ◽

Vol 13 (12) ◽

pp. 4414-4428 ◽

Cited By ~ 82

Author(s):

Marlis Eisenkolb ◽

Christoph Zenzmaier ◽

Erich Leitner ◽

Roger Schneiter

Keyword(s):

Plasma Membrane ◽

Fatty Acid ◽

Double Mutant ◽

Chain Fatty Acid ◽

Long Chain Fatty Acid ◽

Structural Requirement ◽

Fatty Acid Elongase ◽

Synthetically Lethal ◽

Raft Domains ◽

Long Chain

Fungal sphingolipids contain ceramide with a very-long-chain fatty acid (C26). To investigate the physiological significance of the C26-substitution on this lipid, we performed a screen for mutants that are synthetically lethal with ELO3. Elo3p is a component of the ER-associated fatty acid elongase and is required for the final elongation cycle to produce C26 from C22/C24 fatty acids.elo3Δ mutant cells thus contain C22/C24- instead of the natural C26-substituted ceramide. We now report that under these conditions, an otherwise nonessential, but also fungal-specific, structural modification of the major sterol of yeast, ergosterol, becomes essential, because mutations in ELO3 are synthetically lethal with mutations in ERG6. Erg6p catalyzes the methylation of carbon atom 24 in the aliphatic side chain of sterol. The lethality of an elo3Δ erg6Δ double mutant is rescued by supplementation with ergosterol but not with cholesterol, indicating a vital structural requirement for the ergosterol-specific methyl group. To characterize this structural requirement in more detail, we generated a strain that is temperature sensitive for the function of Erg6p in an elo3Δ mutant background. Examination of raft association of the GPI-anchored Gas1p and plasma membrane ATPase, Pma1p, in the conditional elo3Δ erg6 ts double mutant, revealed a specific defect of the mutant to maintain raft association of preexisting Pma1p. Interestingly, in an elo3Δ mutant at 37°C, newly synthesized Pma1p failed to enter raft domains early in the biosynthetic pathway, and upon arrival at the plasma membrane was rerouted to the vacuole for degradation. These observations indicate that the C26 fatty acid substitution on lipids is important for establishing raft association of Pma1p and stabilizing the protein at the cell surface. Analysis of raft lipids in the conditional mutant strain revealed a selective enrichment of ergosterol in detergent-resistant membrane domains, indicating that specific structural determinants on both sterols and sphingolipids are required for their association into raft domains.

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A long-chain fatty acid elongase Elovl6 regulates mechanical damage–induced keratinocyte death and skin inflammation

10.1101/264838 ◽

2018 ◽

Author(s):

Yoshiyuki Nakamura ◽

Takashi Matsuzaka ◽

Satoko Tahara-Hanaoka ◽

Kazuko Shibuya ◽

Hitoshi Shimano ◽

...

Keyword(s):

Fatty Acid ◽

Skin Diseases ◽

Vaccenic Acid ◽

Mechanical Damage ◽

Skin Inflammation ◽

Chain Fatty Acid ◽

Tape Stripping ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase ◽

Long Chain

AbstractMechanical damage on the skin not only affect the barrier function but also induce various immune responses, which trigger or exacerbate the inflammation in healthy individuals and patients with inflammatory skin diseases. However, how mechanical damage-induced skin inflammation is regulated remains largely unknown. Here, we show that mechanical damage due to tape stripping triggered keratinocyte death and release of danger-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein (HMGB-1) and IL-1α, which induced production of proinflammatory cytokines and chemokines IL-1β and CXCL-1 by keratinocytes in mice. We also show that a long-chain fatty acid elongase Elovl6 is expressed in keratinocytes. Mice deficient in Elovl6 had increased epidermal levels of cis-vaccenic acid (CVA); this accelerated keratinocyte death triggered by tape stripping and release of DAMPs and exacerbated skin inflammation. Our results demonstrate that Elovl6 regulates mechanical damage–triggered keratinocyte death and skin inflammation.

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