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

Anna Kutkowska-Kaźmierczak , Małgorzata Rydzanicz , Aleksander Chlebowski , Kamila Kłosowska-Kosicka , Adriana Mika , Jakub Gruchota , Elżbieta Jurkiewicz , Cezary Kowalewski , Agnieszka Pollak , Teresa Joanna Stradomska , Tomasz Kmieć , Rafał Jakubowski , Piotr Gasperowicz , Anna Walczak , Dariusz Śladowski , Ewa Jankowska-Steifer , Lech Korniszewski , Joanna Kosińska , Ewa Obersztyn , Wieslaw Nowak , Tomasz Śledziński , Andrzej Dziembowski , Rafał Płoski


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.
Author Anna Kutkowska-Kaźmierczak
Anna Kutkowska-Kaźmierczak,,
, Małgorzata Rydzanicz
Małgorzata Rydzanicz,,
, Aleksander Chlebowski
Aleksander Chlebowski,,
, Kamila Kłosowska-Kosicka
Kamila Kłosowska-Kosicka,,
, Adriana Mika (FCh / DEA / LChER)
Adriana Mika,,
- Laboratory of Chemical Environmental Risks
, Jakub Gruchota
Jakub Gruchota,,
, Elżbieta Jurkiewicz
Elżbieta Jurkiewicz,,
, Cezary Kowalewski
Cezary Kowalewski,,
, Agnieszka Pollak
Agnieszka Pollak,,
, Teresa Joanna Stradomska
Teresa Joanna Stradomska,,
et al.`
Journal seriesJournal of Medical Genetics, ISSN 0022-2593, (A 40 pkt)
Issue year2018
Publication size in sheets0.5
Keywords in EnglishELOVL1, VLCFA, de novo mutation, neurological disease, skin disease
ASJC Classification2716 Genetics(clinical); 1311 Genetics
Languageen angielski
Score (nominal)40
ScoreMinisterial score = 40.0, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, ArticleFromJournal
Publication indicators WoS Citations = 2; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.737; WoS Impact Factor: 2017 = 5.751 (2) - 2017=5.742 (5)
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