Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy.
Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy.
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DOI：
10.1136/jmedgenet-2015-103457
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发表时间：
2016-06
影响因子：
4
通讯作者：
Elpeleg O
中科院分区：
文献类型：
--
作者：
Edvardson S;Yi JK;Jalas C;Xu R;Webb BD;Snider J;Fedick A;Kleinman E;Treff NR;Mao C;Elpeleg O
脑白质营养不良由于髓鞘的异常生产导致广泛的发病率在生命早期，其遗传背景仍然是未知的。我们的目标是在6-13个月时患有发育退化、脑白质营养不良和周围神经病变的德系犹太人患者中进行分子诊断。外显子组分析，分别使用液相色谱-串联质谱法（LC-MS/MS）和薄层色谱法测定催化C18：1-神经酰胺转化为鞘氨醇和D-核糖-C12-N-（7-硝基苯-2-氧杂-1，3-二唑-4-基）（NBD）-植物神经酰胺转化为NBD-C12-脂肪酸的碱性神经酰胺酶活性，以及通过LC-MS/MS分析患者血液中的鞘脂。患者在编码C18：1-碱性神经酰胺酶和C20：1-碱性神经酰胺酶的ACER 3中为p.E33G纯合。该突变消除了患者细胞中的ACER 3催化活性，并且未能恢复酵母突变株中的碱性神经酰胺酶活性。患者血浆中的ACER 3底物、C18：1-神经酰胺和二氢神经酰胺、C20：1-神经酰胺和二氢神经酰胺以及其他长链神经酰胺和二氢神经酰胺的水平显著增加，沿着复合鞘脂的水平，包括单己糖基神经酰胺和乳糖基神经酰胺。ACER 3基因中p.E33G突变的纯合性导致ACER 3的失活，导致血液中以及可能在脑中的各种鞘脂的积累，这可能是这种新形式的儿童脑白质营养不良的原因。
Leukodystrophies due to abnormal production of myelin cause extensive morbidity in early life; their genetic background is still largely unknown. We aimed at reaching a molecular diagnosis in Ashkenazi-Jewish patients who suffered from developmental regression at 6–13 months, leukodystrophy and peripheral neuropathy. Exome analysis, determination of alkaline ceramidase activity catalysing the conversion of C18:1-ceramide to sphingosine and D-ribo-C12-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-phytoceramide to NBD-C12-fatty acid using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and thin layer chromatography, respectively, and sphingolipid analysis in patients’ blood by LC-MS/MS. The patients were homozygous for p.E33G in the ACER3, which encodes a C18:1-alkaline ceramidase and C20:1-alkaline ceramidase. The mutation abolished ACER3 catalytic activity in the patients’ cells and failed to restore alkaline ceramidase activity in yeast mutant strain. The levels of ACER3 substrates, C18:1-ceramides and dihydroceramides and C20:1-ceramides and dihydroceramides and other long-chain ceramides and dihydroceramides were markedly increased in the patients’ plasma, along with that of complex sphingolipids, including monohexosylceramides and lactosylceramides. Homozygosity for the p.E33G mutation in the ACER3 gene results in inactivation of ACER3, leading to the accumulation of various sphingolipids in blood and probably in brain, likely accounting for this new form of childhood leukodystrophy.
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影响因子：
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作者：
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通讯作者：
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