Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length
Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length
复制标题
DOI：
10.1038/jid.2013.153
复制
发表时间：
2013-09-01
影响因子：
6.5
通讯作者：
Hennies, Hans C.
中科院分区：
文献类型：
--
作者：
Eckl, Katja-Martina;Tidhar, Rotem;Hennies, Hans C.
人类表皮的屏障功能被认为是由角质层中的脂质组成和组织控制的。角化疾病，即鱼鳞病，通常与屏障活性紊乱有关。通过自合性作图和外显子组测序，我们在先天性鱼鳞病患者中发现了 CERS3 纯合错义突变，其特征是出生时有火棉胶膜、全身皮肤鳞屑和轻度红皮病。我们通过 C26-CoA 的 N-酰化测定（在患者角质形成细胞中和使用重组突变蛋白）证明，该突变使皮肤和睾丸中合成的神经酰胺合酶 3 (CerS3) 失活。此外，我们发现在终末分化的患者角质形成细胞中，具有从 C26 到 C34 的很长酰基链的神经酰胺发生了特定的损失，这与最近 CerS3 缺陷小鼠模型的发现一致。对重建患者皮肤的分析显示，表皮分化受到干扰，成熟较早，并且表皮屏障功能受损。我们的研究结果表明，CerS3 合成超长链神经酰胺是皮肤屏障形成的关键早期步骤，并将先天性鱼鳞病的疾病与鞘脂代谢和表皮脂质结构的缺陷联系起来。
The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.