De novo mutation inELOVL1causes ichthyosis,acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy

Abstract

BackgroundVery long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant ELOVL1 mutation. Independently, Kutkowska-Kaźmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects.MethodsWe did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [13C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, in situ hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts.ResultsBoth patients carried an identical heterozygous de novo ELOVL1 mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5’-regions.ConclusionA dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.

Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongaseElovl1

“…The neurography of the peripheral motor and sensory nerves was normal in patients with the ELOVL1 mutation. 17,18 Similarly, Elovl1 −/− Tg(IVL-Elovl1) mice exhibited normal nociceptive responses in the hot plate test ( Figure 4F). These mice also exhibited normal anxiety-like responses in the elevated plus-maze test, mostly normal scores except for a slight decrease in the number of contacts in the social-interaction test, and normal depression-like responses in the Porsolt forced-swim test ( Figure 5).…”

“…Patients with the ELOVL1 mutation exhibited abnormalities related to vision, such as decreased visual acuity, astigmatism, photophobia, and thinning of the nerve fiber layer in the retina. 17,18 Elovl1 −/− Tg(IVL-Elovl1) mice exhibited a tendency to avoid the central area during the first 45 minutes of the open-field test and lower activity levels in the light-dark transition test, despite the lack of detectable retinal histologic abnormality (Figures 4-6). These defects are likely related to differences in luminance, and may be partially relevant to the photophobia observed in one of the two patients.…”

“…In addition to spastic paraplegia of the lower limbs, hypomyelination in the brain, and a hearing deficit at high frequencies, patients with the ELOVL1 mutation exhibit thinning of the nerve fiber layer in the retina, decreased visual acuity, and astigmatism; one patient also exhibited photophobia. 17,18 Therefore, we performed other tests that evaluate neurological functions not limited to motor and auditory functions. The mice were subjected to the light-dark transition test to examine their response to light.…”

“…The patients exhibited ichthyosis symptoms, which are associated with epidermal permeability-barrier dysfunction, resemble the phenotype observed in Elovl1 −/− mice and are likely explained by the reduction in VLC ceramides, especially acylceramides. 14,17,18 The neurological abnormalities of these patients included hypomyelination in the brain, spastic paraplegia, and high-frequency (>2000 Hz) hearing deficit. 17,18 One of the patients also exhibited photophobia.…”

“…14,17,18 The neurological abnormalities of these patients included hypomyelination in the brain, spastic paraplegia, and high-frequency (>2000 Hz) hearing deficit. 17,18 One of the patients also exhibited photophobia. However, the link between the ELOVL1 mutation and these neurological abnormalities remained unclear.…”