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De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy
  1. Noomi Mueller1,2,
  2. Takayuki Sassa3,
  3. Susanne Morales-Gonzalez1,
  4. Joanna Schneider2,4,
  5. Daniel J Salchow5,
  6. Dominik Seelow1,4,
  7. Ellen Knierim1,2,
  8. Werner Stenzel6,
  9. Akio Kihara3,
  10. Markus Schuelke1,2
  1. 1 NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin, Berlin, Germany
  2. 2 Department of Neuropediatrics, Charité–Universitätsmedizin Berlin, Berlin, Germany
  3. 3 Faculty of Pharmaceutical Sciences, Laboratory of Biochemistry, Hokkaido University, Sapporo, Japan
  4. 4 Berlin Institute of Health, Berlin, Germany
  5. 5 Department of Ophthalmology, Charité–Universitätsmedizin Berlin, Berlin, Germany
  6. 6 Institute of Neuropathology, Charité–Universitätsmedizin Berlin, Berlin, Germany
  1. Correspondence to Professor Akio Kihara, Faculty of Pharmaceutical Sciences, Laboratory of Biochemistry, Hokkaido University, Sapporo 060-0812, Japan; kihara{at} and Professor Markus Schuelke, Department of Neuropediatrics, Charité Universitätsmedizin Berlin, Berlin D-13353, Germany; markus.schuelke{at}


Background Very 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.

Methods We 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.

Results Both 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.

Conclusion A dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.

  • hypomyelination
  • very long-chain fatty acids
  • fatty acid synthesis
  • ichthyosis

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  • Contributors NM: analysed and clinically verified the NGS data, did the segregation analyses in the family, cloned the ELOVL1-expression vectors, did the subcellular colocalisation analysis of mutant and wild-type ELOVL1, did the founder haplotype analysis, did the RT-qPCR analysis of mouse tissue, performed the transcriptome analysis, together with MS and TS wrote the first draft of the manuscript. TS: performed the measurement of ceramides and sphingomyelins in the patient fibroblast and skin, the fatty acid elongation assays, and investigated the subcellular localisation of wild-type and mutant ELOVL1 protein. Together with MS and NM wrote the first draft of the manuscript. SM-G: performed cell culture, immunostainings and in situ hybridisation. JS: investigated the patients, provided patient relevant health data. DJS: performed the ophthalmological investigations. DS: provided and programmed software for bioinformatic analyses. EK: supervised patient care and investigation, did molecular genetic analyses. WS: did the light and electron microscopic investigations. AK: directed and supervised the biochemical investigations. MS: conception and supervision of the study, investigated the patients neurologically, performed the bioinformatic analyses of WES and transcriptome analysis, did the genetic counseling of the family, together with NM and TS wrote the first draft of the manuscript. All authors read the final version of the manuscript for intellectual content and consented to its publication.

  • Funding The project was funded by the Deutsche Forschungsgemeinschaft (grant number SFB 665 TP C4 to MS), and the NeuroCure Center of Excellence (grant number Exc 257) as well as by the Advanced Research and Development Programs for Medical Innovation from the Japan Agency for Medical Research and Development (AMED) (AMED-CREST, grant number JP18gm0910002 to AK) and from the Japan Society for the Promotion of Science (JSPS) (KAKENHI grant number JP18H04664 to AK and grant number JP16K08220 to TS), NM was supported by the ’Studienstiftung des deutschen Volkes' and the ’Villigst Studienwerk'.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval The study was approved by the IRBs of the Charité (EA2/107/14) and the Faculty of Pharmaceutical Sciences of Hokkaido University (2017–002).

  • Provenance and peer review Not commissioned; externally peer reviewed.