In Vitro Analysis of LIPH Mutations Causing Hypotrichosis Simplex: Evidence Confirming the Role of Lipase H and Lysophosphatidic Acid in Hair Growth
In Vitro Analysis of LIPH Mutations Causing Hypotrichosis Simplex: Evidence Confirming the Role of Lipase H and Lysophosphatidic Acid in Hair Growth
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DOI：
10.1038/jid.2009.154
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发表时间：
2009-12-01
影响因子：
6.5
通讯作者：
Betz, Regina C.
中科院分区：
文献类型：
--
作者：
Pasternack, Sandra M.;von Kuegelgen, Ivar;Betz, Regina C.
单纯性短毛症是一组可遗传常染色体显性或常染色体隐性遗传的孤立性脱发。脱发通常开始于儿童早期，是弥漫性和渐进性的。编码脂肪酶成员H的LIPH的突变最近被证明导致常染色体隐性形式的HS。在这里，我们描述了一例奥地利HS患者，他被发现携带LIPH基因的复合杂合突变：7bp移码重复(c.403_409dup；p.Gln137HisfsX1)和最近报道的30个氨基酸的框内重复(c.280_369dup；p.Gly94_Lys123dup)。为了检测LIPH突变对脂质代谢的影响，我们建立了一种体外实验来测量这种磷脂酶在基于细胞的系统中的作用。7个碱基的重复移码突变和所有已知的框内突变都能降低脂肪酶的体外活性，以响应脂肪酶H的底物磷脂酸的添加。溶血磷脂酸(LPA)的减少导致表达人G蛋白偶联受体p2y5(P2y5)受体的细胞的反应减弱。我们的研究增加了已知LIPH突变的光谱，并为脂肪酶H及其产物LPA在人类头发生长中的重要作用提供了生化证据。
Hypotrichosis simplex (HS) is a group of isolated alopecias that can be inherited as an autosomal-dominant or an autosomal-recessive trait. Hair loss usually begins in early childhood, and is diffuse and progressive. Mutations in LIPH, which encodes lipase member H, have recently been shown to cause an autosomal-recessive form of HS. Here we describe an Austrian HS patient who was found to be carrying compound heterozygous mutations in the LIPH gene: a 7-bp frameshift duplication (c.403_409dup; p.Gln137HisfsX1) and a recently reported 30-amino acid in-frame duplication (c.280_369dup; p.Gly94_Lys123dup). To examine the impact of LIPH mutations on lipid metabolism, we established an in vitro assay to measure the action of this phospholipase in a cell-based system. Both the 7-bp duplication frameshift mutation and all known in-frame mutations were observed to reduce the in vitro activity of the lipase in response to the addition of phosphatidic acid, the substrate of lipase H. The reduced production of lysophosphatidic acid (LPA) led to a reduced response of cells expressing the human G-protein-coupled receptor p2y5 (p2y5) receptor. Our study increases the spectrum of known LIPH mutations and provides biochemical evidence for the important role of lipase H and its product LPA in human hair growth.