Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development
Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development
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DOI：
10.1073/pnas.0431186100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Miner, JH
中科院分区：
文献类型：
--
作者：
Moulson, CL;Martin, DR;Miner, JH
无皱纹（wrinfr）是一种以前没有特征的、自发的、常染色体隐性遗传的小鼠突变，导致皮肤非常紧、厚。WRFR突变小鼠表现出严重的呼吸困难，继发于它们的皮肤紧绷，并在出生后不久死亡。这种表型与一种非常罕见的人类遗传性疾病限制性皮肤病惊人地相似。WRFR突变小鼠显示出缺陷的皮肤屏障，该屏障通常由皮质包膜（correction envelope）赋予，皮质包膜是蛋白质和脂质的复合物，其防止水分从内部损失和潜在有害物质从外部进入。此外，移植的wrfr皮肤的毛发生长也会受到影响。wrfr突变的定位克隆揭示了一个反转录转座子插入到Slc 27 a4的编码外显子中，该基因编码脂肪酸转运蛋白（FATP）4。FATP 4是主要的肠道FATP，被认为在膳食脂肪酸摄取中起主要作用;因此，它被视为预防或逆转肥胖的靶点。然而，其在体内的功能尚未确定。我们的研究结果表明，FATP 4在皮肤和毛发发育中具有意想不到的关键作用，并表明Slc 27 a4是限制性皮肤病的候选基因。
Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, restrictive dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for restrictive dermopathy.