Evidence that Griscelli Syndrome with Neurological Involvement Is Caused by Mutations in RAB27A, Not MYO5A

Abstract

Griscelli syndrome (GS), a rare autosomal recessive disorder, is characterized by partial albinism, along with immunologic abnormalities or severe neurological impairment or both. Mutations in one of two different genes on chromosome 15q can cause the different subtypes of GS. Most patients with GS display the hemophagocytic syndrome and have mutations in RAB27A, which codes for a small GTPase. Two patients with neurological involvement have mutations in MYO5A, which codes for an actin-based molecular motor. The RAB27A and MYO5A gene products interact with each other and function in vesicle trafficking. We report the molecular basis of GS in a Muslim Arab kindred whose members have extremely variable neurological involvement, along with the hemophagocytic syndrome and immunologic abnormalities. The patients have normal MYO5A genes but exhibit a homozygous 67.5-kb deletion that eliminates RAB27A mRNA and immunocytofluorescence-detectable protein. We also describe the molecular organization of RAB27A and a multiplex polymerase chain reaction assay for the founder deletion in this kindred. Finally, we propose that all patients with GS have RAB27A mutations and immunologic abnormalities that sometimes result in secondary neurological involvement. The two patients described elsewhere who have MYO5A mutations and neurological complications but no immunologic defects may not have GS but instead may have Elejalde syndrome, a condition characterized by mild hypopigmentation and severe, primary neurological abnormalities.

Hematopoietic stem cell transplantation in Griscelli syndrome type 2: a single-center report on 10 patients

“…Spontaneous recovery from an HLH episode has been reported in another GS2 patient, who experienced recurrent episodes with a fatal outcome several years later. 28 In contrast, spontaneous survival of HLH without treatment is very rare in patients with complete perforin deficiency. Our present observations also correspond to those made in murine models, since Rab27a-deficient mice had spontaneous control and better survival rates of HLH than perforin-deficient mice.…”

A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome

“…[3,5,39,40]. Only four disease-causing RAB27A missense mutations have been described in GSII patients.…”

“…Griscelli syndrome (GS) is an autosomal recessive disorder characterized by various degrees of skin hypopigmentation and silver-colored hair accompanied by immunologic impairment and/or defects in the central nervous system [1,2,3]. Three different genes are associated with GS in humans [4,5,6].…”

Role of Rab27 in synaptic transmission at the squid giant synapse

“…For instance, mutations in the RAB27A gene have been shown to cause human type II Griscelli syndrome (15), which is characterized by silvery hair (i.e., defect in melanosome transport in melanocytes) and immunodeficiency (i.e., defect in lytic granule exocytosis in cytotoxic T lymphocytes). Interestingly, some such patients show neurological disorders (16), suggesting an important role of Rab27 in the brain function.…”