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.
journal_name
J Med Genetjournal_title
Journal of medical geneticsauthors
Kutkowska-Kaźmierczak A,Rydzanicz M,Chlebowski A,Kłosowska-Kosicka K,Mika A,Gruchota J,Jurkiewicz E,Kowalewski C,Pollak A,Stradomska TJ,Kmieć T,Jakubowski R,Gasperowicz P,Walczak A,Śladowski D,Jankowska-Steifer E,Korniszedoi
10.1136/jmedgenet-2017-105172subject
Has Abstractpub_date
2018-06-01 00:00:00pages
408-414issue
6eissn
0022-2593issn
1468-6244pii
jmedgenet-2017-105172journal_volume
55pub_type
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