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

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.

Congenital neutropenia: diagnosis, molecular bases and patient management

“…Most genetic defects associated with these disorders have now been identified, and we will only recall the main phenotypes, of which the principal extra-hematopoeitic manifestation is complete or partial albinism [115-117]. …”

Mechanisms of Protein Delivery to Melanosomes in Pigment Cells

“…This enables transfer of melanosomes from microtubules onto the peripheral actin network of skin melanocytes, allowing for subsequent transfer to keratinocytes. Mutations in the genes encoding either RAB27A, melanophilin or myosin VA lead to abnormal perinuclear clu stering of melanosomes (4) and give rise respectively to the hypopigmentation phenotype of ashen , leaden , and dilute mice, models of three subtypes of Griscelli Syndrome (122, 123, 140, 197; Table 1). A similar RAB27A-containing tripartite complex, with a distinct adaptor (MyRIP) and myosin motor (MyoVIIa), maintains peripheral accumulation of melanosomes in the apical domain of retinal pigment epithelia (117).…”

The role of myosin Va in secretory granule trafficking and exocytosis

“…In humans, mutations of myosin Va (MYO5A) lead to Griscelli syndrome, a rare autosomal recessive disorder, with two different types of clinical manifestation, hypopigmentation and neurological impairment. MYO5A mutations that result in a deletion of exon F lead to Griscelli syndrome type 3 and are characterized by hypopigmentation only [39]. MYO5A mutations that affect other regions of exon F lead to Griscelli syndrome type 1, which is characterized by severe primary neurological impairment in addition to hypopigmentation [40].…”