2. Academic Validation
  3. Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features

Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features

  • J Med Genet. 2018 Jun;55(6):408-414. doi: 10.1136/jmedgenet-2017-105172.
Anna Kutkowska-Kaźmierczak # 1,  Małgorzata Rydzanicz # 2,  Aleksander Chlebowski 3,  Kamila Kłosowska-Kosicka 3,  Adriana Mika 4 5,  Jakub Gruchota 3,  Elżbieta Jurkiewicz 6,  Cezary Kowalewski 7,  Agnieszka Pollak 8,  Teresa Joanna Stradomska 9,  Tomasz Kmieć 10,  Rafał Jakubowski 11 12,  Piotr Gasperowicz 2,  Anna Walczak 2,  Dariusz Śladowski 13,  Ewa Jankowska-Steifer 14,  Lech Korniszewski 8,  Joanna Kosińska 2,  Ewa Obersztyn 1,  Wieslaw Nowak 15,  Tomasz Śledziński 5,  Andrzej Dziembowski 3,  Rafał Płoski 2
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland.
  • 2 Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
  • 3 Laboratory of RNA Biology and Functional Genomics, Polish Academy of Sciences, Warsaw, Poland.
  • 4 Department of Environmental Analysis, Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
  • 5 Department of Pharmaceutical Biochemistry, Medical University of Gdansk, Gdansk, Poland.
  • 6 Department of Diagnostic Imaging, The Children's Memorial Health Institute, Warsaw, Poland.
  • 7 Department of Dermatology and Immunodermatology, Medical University of Warsaw, Warsaw, Poland.
  • 8 Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland.
  • 9 Department of Biochemistry, Radioimmunology and Experimental Medicine, Children's Memorial Health Institute, Warsaw, Poland.
  • 10 Child Neurology Department, The Children's Memorial Health Institute, Warsaw, Poland.
  • 11 Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, Poland.
  • 12 Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  • 13 Department of Transplantology and Central Tissue Bank, Centre for Biostructure, Medical University of Warsaw, Warsaw, Poland.
  • 14 Department of Histology and Embryology, Warsaw Medical University, Warsaw, Poland.
  • 15 Institue of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, Poland.
  • # Contributed equally.
PMID: 29496980 DOI: 10.1136/jmedgenet-2017-105172
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.

Keywords

ELOVL1; VLCFA; de novo mutation; neurological disease; skin disease.

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