Ménasché Gaël, Ho Chen Hsuan, Sanal Ozden, Feldmann Jérôme, Tezcan Ilhan, Ersoy Fügen, Houdusse Anne, Fischer Alain, de Saint Basile Geneviève
Unité de Recherhe sur le Développement Normal et Pathologique du Systéme Immunitaire, Hôpital Necker-Enfants Malades, Paris, France.
J Clin Invest. 2003 Aug;112(3):450-6. doi: 10.1172/JCI18264.
Griscelli syndrome (GS) is a rare autosomal recessive disorder that associates hypopigmentation, characterized by a silver-gray sheen of the hair and the presence of large clusters of pigment in the hair shaft, and the occurrence of either a primary neurological impairment or a severe immune disorder. Two different genetic forms, GS1 and GS2, respectively, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin Va (MyoVa) cause GS1 and the dilute mutant in mice, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2 and the ashen mouse model. We herein present genetic and functional evidence that a third form of GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin (Mlph), the ortholog of the gene mutated in leaden mice. We also show that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis, which in part remain to be unraveled.
格里塞利综合征（GS）是一种罕见的常染色体隐性疾病，其特征为色素减退，表现为头发呈银灰色光泽且毛干中有大量色素团簇，同时伴有原发性神经功能障碍或严重免疫紊乱。GS有两种不同的遗传形式，即GS1和GS2，分别对应相互排斥的神经学和免疫学表型。编码分子运动蛋白肌球蛋白Va（MyoVa）的基因突变导致GS1以及小鼠中的稀释突变体，而编码小GTP酶Rab27a的基因突变则是GS2和灰白色小鼠模型的病因。我们在此提供遗传和功能证据，表明GS的第三种形式（GS3），其表现仅限于GS特有的色素减退，是由编码黑素亲和蛋白（Mlph）的基因突变引起的，Mlph是铅灰色小鼠中发生突变的基因的直系同源物。我们还表明，MYO5A F外显子的缺失也可导致相同的表型，该外显子具有组织限制性表达模式。GS的这种谱系明确了黑素细胞、神经元和免疫细胞在分泌颗粒胞吐作用中所使用的不同分子途径，其中部分途径仍有待阐明。
