Cellular and clinical report of new Griscelli syndrome type III cases

Abstract

Summary 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 (SHD) 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.

Rab27 Effectors, Pleiotropic Regulators in Secretory Pathways

“…Dysfunctions of downstream targets of Rab27 or its regulators are also expected to be found to cause diseases that are characterized by secretory defects (156) (see Table 1). Actually, dysfunctions of Slac2-a and Munc13-4 have already been shown to cause type 3 Griscelli syndrome (mouse model: leaden), whose patients show silvery hair (73,74), and type 3 familial hemophagocytic lymphohistiocytosis (FHL3) (mouse model: jinx) (103)(104)(105), respectively. Secretion defects have been identified in several Slp KO mice (22,25,26,29,42) and Noc2 KO mice (98), e.g.…”

Genetic 3′UTR variation is associated with human pigmentation characteristics and sensitivity to sunlight

“…MLPH encodes a member of the exophilin subfamily of Rab effector proteins known as melanophilin, which acts as a link between the small GTPase melanosome‐bound RAB27A and the actin‐associated motor protein MYO5A . This protein complex plays a crucial role in the melanosome motility in melanocytes, and aberrations in any of the complex components have been shown to result in perinuclear localisation of melanosomes and therefore failure to transfer mature melanosomes to adjacent keratinocytes, eventually causing hypopigmentation . Human individuals homozygous for a pathogenic MLPH mutation (c.102C>T; p.R35W) display Griscelli syndrome type 3, a pigmentary disorder characterized by a hypopigmented phenotype .…”

“…This protein complex plays a crucial role in the melanosome motility in melanocytes, and aberrations in any of the complex components have been shown to result in perinuclear localisation of melanosomes and therefore failure to transfer mature melanosomes to adjacent keratinocytes, eventually causing hypopigmentation . Human individuals homozygous for a pathogenic MLPH mutation (c.102C>T; p.R35W) display Griscelli syndrome type 3, a pigmentary disorder characterized by a hypopigmented phenotype . The naevus‐associated SNP in this work, rs2325813, is predicted to disrupt a binding site of two miRNAs (hsa‐miR‐185‐3p and hsa‐miR‐762).…”

Griscelli syndrome type 3‐like phenotype with MYO‐5A exon‐F deletion

“…GS3 manifestations are restricted to hypopigmentation of the skin and silvery-gray hair. There is no neurological symptom and immune defect in this type of GS (5,7,10). These patients may remain undiagnosed because the only symptom is the pigmentary dilution.…”