Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.
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Kutkowska-Kazmierczak A, Rydzanicz M, Chlebowski A, Klosowska-Kosicka K, Mika A, Gruchota J, Jurkiewicz E, Kowalewski C, Pollak A, Stradomska TJ, Kmiec T, Jakubowski R, Gasperowicz P, Walczak A, Sladowski D, Jankowska-Steifer E, Korniszewski L, Kosinska J, Obersztyn E, Nowak W, Sledzinski T, Dziembowski A, Ploski R
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. Epub 2018 Mar 1.
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- 29496980 [ View in PubMed]
- 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=7.8x10(-6) vs HEK293 cells with wild type (wt) construct, no difference vs naive HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3x10(-7), P=1.2x10(-5), for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2x10(-7), P=1.9x10(-4), respectively, comparison vs naive 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.