Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

Hopiavuori, Blake R.; Deák, F.; Wilkerson, Joseph L.; Brush, Richard S.; Rocha-Hopiavuori, Nicole A.; Hopiavuori, Austin; Ozan, Kathryn G.; Sullivan, Michael T.; Wren, Jonathan D.; Georgescu, Constantin; Szweda, Luke I.; Awasthi, Vibhudutta; Towner, Rheal A.; Sherry, David M.; Anderson, Robert E.; Agbaga, Martin-Paul

doi:10.1007/s12035-017-0824-8

Cited by 33 publications

(114 citation statements)

References 65 publications

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“…The W246G ELOVL4 mutation examined here selectively impaired synthesis of VLC-SFA, with no significant effect on VLC-PUFA synthesis, leading to compromised ERG responses in MUT rats in the absence of retinal degeneration. These results are consistent with the aberrant presynaptic release and seizures induced by VLC-SFA deficiency due to homozygous knock-in of the 5-base-pair STGD3 mutation [3]. The appearance of EKV in only MUT rats is also consistent with the VLC-SFA deficiency associated with homozygous W246G ELOVL4 mutation.…”

Section: Discussionsupporting

confidence: 84%

“…Therefore, the birth and survival of MUT rats were unexpected and presented a unique opportunity to further explore ELOVL4 function. ELOVL4 is essential for synthesis of both VLC-PUFA and VLC-SFA [1][2][3]. In the retina, VLC-PUFA are the main product and are incorporated into PC and concentrated in the outer segment membranes [15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

“…Our meticulous recent lipidomic analysis of mouse [7], rat, and baboon [3] brains using modern analytical tools found VLC-SFA (28:0 and 30:0). These VLC-SFA were incorporated into complex sphingolipids and were enriched in synaptic vesicles prepared from baboon hippocampus, where they contribute to the regulation of presynaptic neurotransmitter release [3,8]. Previous studies have reported phosphatidylcholine containing VLC-PUFA in early postnatal rat brain and in the brains of human patients with Zellweger's disease, a peroxisomal disorder that disrupts lipid metabolism [9,10], but no VLC-PUFA have been reported in the healthy mature brain.…”

Section: Introductionmentioning

confidence: 98%

“…Elo ngation of v ery l ong chain fatty acids- 4 (ELOVL4) catalyzes the first, rate-limiting step in the synthesis of very long chain polyunsaturated and saturated fatty acids with fatty acid chain lengths of 28 carbons or more [VLC-PUFA and VLC-SFA, respectively [ 1 – 3 ]]. ELOVL4 is the only known fatty acid elongase that performs this function [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…Expression of ELOVL4 is limited to a small number of organs including the retina, brain, skin, testes, and Meibomian gland [ 4 – 6 ], which show tissue-specific VLC-PUFA and VLC-SFA profiles. Our meticulous recent lipidomic analysis of mouse [ 7 ], rat, and baboon [ 3 ] brains using modern analytical tools found VLC-SFA (28:0 and 30:0). These VLC-SFA were incorporated into complex sphingolipids and were enriched in synaptic vesicles prepared from baboon hippocampus, where they contribute to the regulation of presynaptic neurotransmitter release [ 3 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration

et al. 2020

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Elongation of very long chain fatty acids-4 (ELOVL4) is essential for synthesis of very long chain polyunsaturated and saturated fatty acids (VLC-PUFA and VLC-SFA, respectively) of chain length greater than 26 carbons. Mutations in the ELOVL4 gene cause several distinct neurodegenerative diseases including Stargardt-like macular dystrophy (STGD3), spinocerebellar ataxia 34 (SCA34), and a neuro-ichthyotic syndrome with severe seizures and spasticity, as well as erythrokeratitis variabilis (EKV), a skin disorder. However, the relationship between ELOVL4 mutations, its VLC-PUFA and VLC-SFA products, and specific neurological symptoms remains unclear. We generated a knock-in rat line (SCA34-KI) that expresses the 736T>G (p.W246G) form of ELOVL4 that causes human SCA34. Lipids were analyzed by gas chromatography and mass spectrometry. Retinal function was assessed using electroretinography. Retinal integrity was assessed by histology, optical coherence tomography, and immunolabeling. Analysis of retina and skin lipids showed that the W246G mutation selectively impaired synthesis of VLC-SFA, but not VLC-PUFA. Homozygous SCA34-KI rats showed reduced ERG a- and b-wave amplitudes by 90 days of age, particularly for scotopic responses. Anatomical analyses revealed no indication of neurodegeneration in heterozygote or homozygote SCA34-KI rats out to 6–7 months of age. These studies reveal a previously unrecognized role for VLC-SFA in regulating retinal function, particularly transmission from photoreceptors to the inner retina, in the absence of neurodegeneration. Furthermore, these findings suggest that the tissue specificity and symptoms associated with disease-causing ELOVL4 mutations likely arise from selective differences in the ability of the mutant ELOVL4 enzymes to support synthesis of VLC-PUFA and/or VLC-SFA.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration

et al. 2020

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Expanding the allelic spectrum of ELOVL4‐related autosomal recessive neuro‐ichthyosis

Alabdulrazzaq,

Alanzi,

Al‐Balool

et al. 2023

Molec Gen & Gen Med

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BackgroundVery long‐chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt‐like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single‐nucleotide variants.MethodsWe performed clinical exome sequencing on probands from four unrelated families with neuro‐ichthyosis.ResultsWe identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three.ConclusionOur study expands the allelic spectrum of ELOVL4‐related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

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W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

et al. 2021

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Spinocerebellar ataxia (SCA) is a neurodegenerative disorder characterized by ataxia and cerebellar atrophy. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is caused by mutations in ELOVL4 (ELOngation of Very Long-chain fatty acids 4), a fatty acid elongase essential for biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons), which have important functions in the brain, skin, retina, Meibomian glands, testes, and sperm. We generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. Rats carrying the mutation developed impaired motor deficits by 2 months of age. To understand the mechanism of these motor deficits, we performed electrophysiological studies using cerebellar slices from rats homozygous for W246G mutant ELOVL4 and found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells. Neuroanatomical analysis of the cerebellum showed normal cytoarchitectural organization with no evidence of degeneration out to 6 months of age. These results point to ELOVL4 as essential for motor function and cerebellar synaptic plasticity. The results further suggest that ataxia in SCA34 patients may arise from a primary impairment of synaptic plasticity and cerebellar network desynchronization before onset of neurodegeneration and progression of the disease at a later age.

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Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

Cited by 33 publications

References 65 publications

The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration

The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration

Expanding the allelic spectrum of ELOVL4‐related autosomal recessive neuro‐ichthyosis

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

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