Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda MD, USA.
Pigment Cell Melanoma Res. 2012 Jan;25(1):47-56. doi: 10.1111/j.1755-148X.2011.00901.x. Epub 2011 Oct 3.
The RAB27A/Melanophilin/Myosin-5a tripartite protein complex is required for capturing mature melanosomes in the peripheral actin network of melanocytes for subsequent transfer to keratinocytes. Mutations in any one member of this tripartite complex cause three forms of Griscelli syndrome (GS), each with distinct clinical features but with a similar cellular phenotype. To date, only one case of GS type III (GSIII), caused by mutations in the Melanophilin (MLPH) gene, has been reported. Here, we report seven new cases of GSIII in three distinct Arab pedigrees. All affected individuals carried a homozygous missense mutation (c.102C>T; p.R35W), located in the conserved Slp homology domain of MLPH, and had hypomelanosis of the skin and hair. We report the first cellular studies on GSIII melanocytes, which demonstrated that MLPH(R35W) causes perinuclear aggregation of melanosomes in melanocytes, typical for GS. Additionally, co-immunoprecipitation assays showed that MLPH(R35W) lost its interaction with RAB27A, indicating pathogenicity of the R35W mutation.
RAB27A/黑素瘤磷蛋白/肌球蛋白-5a 三聚体蛋白复合物对于将成熟的黑素体捕获到黑素细胞外周肌动蛋白网络中，以便随后转移到角质细胞中是必需的。该三聚体复合物中任何一个成员的突变都会导致三种格里塞利综合征（GS）形式，每种形式都有不同的临床特征，但具有相似的细胞表型。迄今为止，只有一例由黑素瘤磷蛋白（MLPH）基因突变引起的 GSIII 型（GSIII）被报道。在这里，我们报告了三个不同阿拉伯血统中 7 例新的 GSIII 病例。所有受影响的个体均携带纯合错义突变（c.102C>T;p.R35W），位于 MLPH 的保守 Slp 同源结构域中，皮肤和头发的黑色素沉着减少。我们报告了对 GSIII 黑素细胞的首次细胞研究，该研究表明 MLPH（R35W）导致黑素细胞中黑素体的核周聚集，这是 GS 的典型特征。此外，共免疫沉淀测定表明 MLPH（R35W）失去了与 RAB27A 的相互作用，表明 R35W 突变具有致病性。
