Cellular and clinical report of new Griscelli syndrome type III cases

被引:23
作者
Westbroek, Wendy [1 ]
Klar, Aharon [2 ]
Cullinane, Andrew R. [1 ]
Ziegler, Shira G. [1 ]
Hurvitz, Haggit [2 ]
Ganem, Ashraf [2 ]
Wilson, Kirkland [1 ]
Dorward, Heidi [1 ]
Huizing, Marjan [1 ]
Tamimi, Haled [2 ]
Vainshtein, Igor [2 ]
Berkun, Yackov [3 ,4 ]
Lavie, Moran [3 ,4 ]
Gahl, William A. [1 ]
Anikster, Yair [3 ,4 ]
机构
[1] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA
[2] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pediat, Bikur Cholim Gen Hosp, IL-91010 Jerusalem, Israel
[3] Edmond & Lily Safra Childrens Hosp, Metab Dis Unit, Sheba Med Ctr, Tel Hashomer, Israel
[4] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel
基金
美国国家卫生研究院;
关键词
Griscelli syndrome type III; Melanophilin; melanocyte; melanosome; Myosin-5a; RAB27A; tripartite complex; SMALL GTPASE RAB27B; MYOSIN-VA; MELANOSOME TRANSPORT; HUMAN MELANOCYTES; LINKS RAB27A; MELANOPHILIN; MUTATIONS; PROTEINS; SLAC2-A/MELANOPHILIN; DISEASE;
D O I
10.1111/j.1755-148X.2011.00901.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:47 / 56
页数:10
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