TY - JOUR
T1 - Cellular and clinical report of new Griscelli syndrome type III cases
AU - Westbroek, Wendy
AU - Klar, Aharon
AU - Cullinane, Andrew R.
AU - Ziegler, Shira G.
AU - Hurvitz, Haggit
AU - Ganem, Ashraf
AU - Wilson, Kirkland
AU - Dorward, Heidi
AU - Huizing, Marjan
AU - Tamimi, Haled
AU - Vainshtein, Igor
AU - Berkun, Yackov
AU - Lavie, Moran
AU - Gahl, William A.
AU - Anikster, Yair
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - Griscelli syndrome type III
KW - Melanocyte
KW - Melanophilin
KW - Melanosome
KW - Myosin-5a
KW - RAB27A
KW - Tripartite complex
UR - http://www.scopus.com/inward/record.url?scp=83955164233&partnerID=8YFLogxK
U2 - 10.1111/j.1755-148X.2011.00901.x
DO - 10.1111/j.1755-148X.2011.00901.x
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C2 - 21883982
AN - SCOPUS:83955164233
SN - 1755-1471
VL - 25
SP - 47
EP - 56
JO - Pigment Cell and Melanoma Research
JF - Pigment Cell and Melanoma Research
IS - 1
ER -