Institut National de Santé et de Recherche Médical (INSERM), U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biology and Pathology of Melanocytes, Nice, France.
FASEB J. 2012 Sep;26(9):3779-89. doi: 10.1096/fj.11-201376. Epub 2012 May 30.
Cystinosis is a rare autosomal recessive disease characterized by cystine crystal accumulation leading to multiorgan dysfunctions and caused by mutation in CTNS. CTNS encodes cystinosin, a cystine/H(+) symporter that exports cystine out of the lysosomes. Patients with cystinosis frequently exhibit blond hair and fair complexion, suggesting an alteration in melanogenesis. However, the pigmentation singularities of these patients have not been studied, and the role of cystinosin in melanogenesis has remained unknown. In our study, a clinical evaluation of 27 patients with cystinosis showed that 44% had a cutaneous pigmentation dilution compared to their relatives. Analysis of the hair melanin content in these patients by HPLC demonstrated a 50% decrease in eumelanin (4360 vs. 9360 ng/mg), and a 2-fold increase in pheomelanin (53 vs. 20 ng/mg), the yellow/red pigments. Cystinosin-deficient mice also showed a 4-fold increase in hair pheomelanin content. In vitro studies showed that cystinosin was located at melanosomes. CTNS silencing led to a 75% reduction of melanin synthesis that was caused by a degradation of tyrosinase by lysosomal proteases. Our results objectify the pigmentation defect in patients with cystinosis. We also identify the role of CTNS in melanogenesis and add a new gene to the list of the genes involved in the control of skin and hair pigmentation.
胱氨酸贮积症是一种罕见的常染色体隐性遗传病，其特征是胱氨酸晶体积累导致多器官功能障碍，由 CTNS 基因突变引起。CTNS 编码胱氨酸/ H(+) 转运蛋白，可将胱氨酸从溶酶体中输出。胱氨酸贮积症患者常表现为金黄色头发和浅色皮肤，表明黑色素生成发生改变。然而，这些患者的色素沉着特征尚未得到研究，胱氨酸转运蛋白在黑色素生成中的作用仍不清楚。在我们的研究中，对 27 名胱氨酸贮积症患者进行临床评估，发现与亲属相比，44%的患者皮肤色素沉着稀释。通过 HPLC 分析这些患者的头发黑色素含量，发现真黑色素（4360 与 9360ng/mg）减少 50%，黄/红色素（pheomelanin）增加 2 倍（53 与 20ng/mg）。胱氨酸转运蛋白缺陷小鼠的头发 pheomelanin 含量也增加了 4 倍。体外研究表明，胱氨酸转运蛋白位于黑素体上。CTNS 沉默导致黑色素合成减少 75%，这是由溶酶体蛋白酶降解酪氨酸酶引起的。我们的研究结果客观地描述了胱氨酸贮积症患者的色素沉着缺陷。我们还确定了 CTNS 在黑色素生成中的作用，并将一个新基因添加到控制皮肤和头发色素沉着的基因列表中。
