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Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features
  1. Anna Kutkowska-Kaźmierczak1,
  2. Małgorzata Rydzanicz2,
  3. Aleksander Chlebowski3,
  4. Kamila Kłosowska-Kosicka3,
  5. Adriana Mika4,5,
  6. Jakub Gruchota3,
  7. Elżbieta Jurkiewicz6,
  8. Cezary Kowalewski7,
  9. Agnieszka Pollak8,
  10. Teresa Joanna Stradomska9,
  11. Tomasz Kmieć10,
  12. Rafał Jakubowski11,12,
  13. Piotr Gasperowicz2,
  14. Anna Walczak2,
  15. Dariusz Śladowski13,
  16. Ewa Jankowska-Steifer14,
  17. Lech Korniszewski8,
  18. Joanna Kosińska2,
  19. Ewa Obersztyn1,
  20. Wieslaw Nowak15,
  21. Tomasz Śledziński5,
  22. Andrzej Dziembowski3,
  23. Rafał Płoski2
  1. 1Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland
  2. 2Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
  3. 3Laboratory of RNA Biology and Functional Genomics, Polish Academy of Sciences, Warsaw, Poland
  4. 4Department of Environmental Analysis, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
  5. 5Department of Pharmaceutical Biochemistry, Medical University of Gdansk, Gdansk, Poland
  6. 6Department of Diagnostic Imaging, The Children’s Memorial Health Institute, Warsaw, Poland
  7. 7Department of Dermatology and Immunodermatology, Medical University of Warsaw, Warsaw, Poland
  8. 8Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland
  9. 9Department of Biochemistry, Radioimmunology and Experimental Medicine, Children’s Memorial Health Institute, Warsaw, Poland
  10. 10Child Neurology Department, The Children’s Memorial Health Institute, Warsaw, Poland
  11. 11Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, Poland
  12. 12Centre of New Technologies, University of Warsaw, Warsaw, Poland
  13. 13Department of Transplantology and Central Tissue Bank, Centre for Biostructure, Medical University of Warsaw, Warsaw, Poland
  14. 14Department of Histology and Embryology, Warsaw Medical University, Warsaw, Poland
  15. 15Institue of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, Poland
  1. Correspondence to Professor Rafał Płoski, Department of Medical Genetics, Medical University of Warsaw, Warsaw 02-106, Poland; rploski{at}wp.pl

Abstract

Background Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function.

Objectives To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease.

Methods Whole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography–mass spectrometry in stably transfected HEK2932 cells and in cultured patient’s fibroblasts.

Results Probands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8×10−6 vs HEK293 cells with wild type (wt) construct, no difference vs naïve HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3×10−7, P=1.2×10−5, for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2×10−7, P=1.9×10−4, respectively, comparison vs naïve HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient’s fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0–C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased.

Conclusion The ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD.

  • VLCFA
  • ELOVL1
  • skin disease
  • neurological disease
  • de novo mutation

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Footnotes

  • AK-K and MR contributed equally.

  • Contributors Conceptualisation: RP, MR and AK-K. Methodology: RP, WN, RJ, KK-K and JG. Software: WN and RJ. Validation: AP, PG and AW. Formal analysis: RP, TJS, WN, RJ, TS and AM. Investigation: RP, MR, AP, PG, AW, JK, TJS, WN, RJ, AC, KK, JG, TS, AM, DŚ, AK-K, EJ-S, EJ,CK, TK and EO. Resources: WN, RJ, DS and EJ. Writing: original draft preparation: RP, MR, TJS, AK-K and EJ. Writing: review and editing: RP, MR, TJS, WN, RJ, TS, AM, AK-K and EJ. Visualisation: RP, MR, WN, RJ and EJ. Supervision: RP and AD. Project administration: RP. Funding acquisition: RP and AD.

  • Funding The study was supported by the National Science Centre (NCN) Poland grant 2013/11/B/NZ7/04944 to RP. The work in the AD laboratory was supported by Foundation for Polish Science grant TEAM/2016-1/3. Some of the experiments were carried out with the use of CePT infrastructure (Innovative economy 2007–13, Agreement POIG.02.02.00-14-024/08-00). Calculations were possible due to ICNT UMK infrastructure. Support by Polish Ministry for Science and Higher Education Grant 0003/ID3/2016/64 (Ideas Plus II) is acknowledged (RJ).

  • Competing interests None declared.

  • Patient consent Guardian consent obtained.

  • Ethics approval The study protocol was approved by the Ethical Committee at Warsaw Medical University.

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

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