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Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1)
Gaël Ménasché, … , Alain Fischer, Geneviève de Saint Basile
Gaël Ménasché, … , Alain Fischer, Geneviève de Saint Basile
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):450-456. https://doi.org/10.1172/JCI18264.
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Article Immunology

Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1)

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Abstract

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.

Authors

Gaël Ménasché, Chen Hsuan Ho, Ozden Sanal, Jérôme Feldmann, Ilhan Tezcan, Fügen Ersoy, Anne Houdusse, Alain Fischer, Geneviève de Saint Basile

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Figure 3

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MLPH missense mutation in PA. (a) Detection of MLPH mutation in PA’s fam...
MLPH missense mutation in PA. (a) Detection of MLPH mutation in PA’s family by fluorometric sequencing. DNA sequence analysis of exon 1 shows a C-to-T transition resulting in an R35W substitution in PA. The mutations of the mother and father are heterozygous for R35W. (b) Sequence alignment of the SHD1 domain of human Mlph (MLPH) and mouse Mlph (Mlph) as well as of mouse Rabphilin-3A (mRabphilin-3A). The residue R35 substituted by W in PA is indicated by an arrow, and the seven residues deleted in the leaden mutant are indicated by italics highlighted in gray. The Rabphilin-3A residues mediating the contact with Rab3A (26) are indicated by asterisks. Amino acid numbers are indicated at the right end of each line.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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