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

J Clin Invest. 2003 Aug;112(3):450-6. doi: 10.1172/JCI18264.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • DNA / genetics
  • Exons
  • Female
  • Hair / pathology
  • Humans
  • Hypopigmentation / genetics*
  • Hypopigmentation / metabolism
  • Hypopigmentation / pathology
  • Male
  • Melanosomes / pathology
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Myosin Heavy Chains / genetics*
  • Myosin Type V / genetics*
  • Pedigree
  • Phenotype
  • Sequence Deletion
  • Syndrome
  • rab GTP-Binding Proteins / metabolism
  • rab27 GTP-Binding Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MLPH protein, human
  • Mlph protein, mouse
  • Myo5a protein, mouse
  • rab27 GTP-Binding Proteins
  • MYO5A protein, human
  • DNA
  • Myosin Type V
  • RAB27A protein, human
  • Rab27a protein, mouse
  • Myosin Heavy Chains
  • rab GTP-Binding Proteins