Griscelli disease is a rare autosomal recessive disease occurring during the first days of life and characterized by partial albinism and immunologic abnormalities. The skin is hypopigmented and the hair has a characteristic silvery aspect. Epidermal cells, responsible for producing the natural skin pigment melanin, appear to be defective : vesicles containing newly synthesized melanin accumulate instead of transporting the pigment towards keratinocytes. Patients also have very severe immune abnormalities, principaly characterized by a defect in cytotoxicity and onset of uncontrolled T cells and macrophages proliferation, which infiltrate the various organs. Bone marrow transplantation is the only treatment for this disease, which otherwise can be fatal in childhood.
The "dilute" mouse model shows skin abnormalities resembling those of human disease, especially accumulation of melanin vesicles at the site of production. The gene responsible for the murine condition encodes a protein of the myosin family, myosin-5a. Myosins are proteins that serve as "molecular motors", and run parallel to actin filaments which form the cell skeleton. Some are thought to play a role in intracellular transport. Given the functional abnormalities of Griscelli disease, myosin genes were good candidates.
Geneviève de Saint Basile's team looked for possible genetic links between myosins and Griscelli disease in four affected families. They finally located the gene on chromosome 15, in a region (q21) known to contain genes coding for two myosins, one of which is myosin-5a. They then identified mutations in the myosin-5a gene of two patients.
This finding supports an important role of myosin-5a in organelle transport within cells, especially the conveyancing of melanin-containing vesicles towards specialized skin cells. The relation between the functional defect in myosin-5a remains to be linked to the severe immune abnormalities in Griscelli disease. Might myosin-5a be involved in the transport and, possibly, the expression of molecules with an important role in controling the immune response? A better understanding of the relevant immunological pathways could lead to new therapeutic approaches to this disease, as well as Chediak-Higashi disease which presents with similar symptoms. These results open the way to new research on the links between cell transport and the immune response.
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"Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene"
E.Pastural S, F. J. Barrat §, R. Dufourcq-Lagelouse §, S. Certain §, O. Sanal *, N. Jabadoº, R. Seger #, C. Griscelli º, A. Fischer §º and G. de Saint Basile §
§ INSERM Unit 429 (Normal and pathological development of immune system), Paris
* Hacettepe children's hospital, Ankara, Turkey
º Unité d1immunologie et d1hématologie pédiatrique, Hôpital Necker-Enfants malades, Paris
# Université Kinderspital Zürich, Switzerland
Nature Genetics, July 1997, vol 16, NO. 3, pp. 289-292