先证者
HEK 293细胞
转染
复合杂合度
鱼鳞病
突变
表型
内科学
痉挛
内分泌学
医学
外显子组测序
遗传学
生物
基因
物理疗法
受体
作者
Anna Kutkowska‐Kaźmierczak,Małgorzata Rydzanicz,Aleksander Chlebowski,Kamila Kłosowska-Kosicka,Adriana Mika,Jakub Gruchota,Elżbieta Jurkiewicz,Cezary Kowaléwski,Agnieszka Pollak,Teresa Joanna Stradomska,Tomasz Kmieć,Rafał Jakubowski,Piotr Gasperowicz,Anna Walczak,Dariusz Śladowski,Ewa Jankowska‐Steifer,L Korniszewski,Joanna Kosińska,Ewa Obersztyn,Wiesław Nowak,Tomasz Śledziński,Andrzej Dziembowski,Rafał Płoski
标识
DOI:10.1136/jmedgenet-2017-105172
摘要
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.
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