RGD Reference Report - Characterization of the molecular defects in Rab27a, caused by RAB27A missense mutations found in patients with Griscelli syndrome. - Rat Genome Database

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Characterization of the molecular defects in Rab27a, caused by RAB27A missense mutations found in patients with Griscelli syndrome.

Authors: Bahadoran, P  Busca, R  Chiaverini, C  Westbroek, W  Lambert, J  Bille, K  Valony, G  Fukuda, M  Naeyaert, JM  Ortonne, JP  Ballotti, R 
Citation: Bahadoran P, etal., J Biol Chem. 2003 Mar 28;278(13):11386-92. Epub 2003 Jan 16.
RGD ID: 1601587
Pubmed: PMID:12531900   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M211996200   (Journal Full-text)

Rab27a plays a pivotal role in the transport of melanosomes to dendrite tips of melanocytes and mutations in RAB27A, which impair melanosome transport cause the pigmentary dilution and the immune deficiency found in several patients with Griscelli syndrome (GS). Interestingly, three GS patients present single homozygous missense mutations in RAB27A, leading to W73G, L130P, and A152P transitions that affect highly conserved residues among Rab proteins. However, the functional consequences of these mutations have not been studied. In the present report, we evaluated the effect of overexpression of these mutants on melanosome, melanophilin, and myosin-Va localization in B16 melanoma cells. Then we studied several key parameters for Rab27a function, including GTP binding and interaction with melanophilin/myosin-Va complex, which links melanosomes to the actin network. Our results showed that Rab27a-L130P cannot bind GTP, does not interact with melanophilin, and consequently cannot allow melanosome transport on the actin filaments. Interestingly, Rab27a-W73G binds GTP but does not interact with melanophilin. Thus, Rab27a-W73G cannot support the actin-dependent melanosome transport. Finally, Rab27a-A152P binds both GTP and melanophilin. However, Rab27a-A152P does not allow melanosome transport and acts as a dominant negative mutant, because its overexpression, in B16 melanoma cells, mimics a GS phenotype. Hence, the interaction of Rab27a with melanophilin/myosin-Va is not sufficient to ensure a correct melanosome transport. Our results pointed to an unexpected complexity of Rab27a function and open the way to the search for new Rab27a effectors or regulators that control the transport of Rab27a-dependent vesicles.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RAB27AHumanHypopigmentation  IAGP Griscelli syndrome type 2 more ...RGD 
Rab27aRatHypopigmentation  ISORAB27A (Homo sapiens)Griscelli syndrome type 2 more ...RGD 
Rab27aMouseHypopigmentation  ISORAB27A (Homo sapiens)Griscelli syndrome type 2 more ...RGD 
RAB27AHumannon-Langerhans-cell histiocytosis  IAGP Griscelli syndrome type 2 more ...RGD 
Rab27aRatnon-Langerhans-cell histiocytosis  ISORAB27A (Homo sapiens)Griscelli syndrome type 2 more ...RGD 
Rab27aMousenon-Langerhans-cell histiocytosis  ISORAB27A (Homo sapiens)Griscelli syndrome type 2 more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rab27a  (RAB27A, member RAS oncogene family)

Genes (Mus musculus)
Rab27a  (RAB27A, member RAS oncogene family)

Genes (Homo sapiens)
RAB27A  (RAB27A, member RAS oncogene family)


Additional Information