A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome.
The autosomal recessive Griscelli syndrome type II (GSII) is caused by mutations in the RAB27A gene. Typical clinical features include immunological impairment, silver-gray scalp hair, eyelashes and eyebrows and hypomelanosis of the skin. Rabs help determine the specificity of membrane trafficking steps within cells. In melanocytes, the GTP-bound form of Rab27A associates with the membranes of mature fully-pigmented melanosomes through its geranylgeranyl group. Once attached, Rab27A recruits the downstream effector Melanophilin (Mlph) and the actin-dependent motor protein Myosin Va (MyoVa). The molecular Rab27A/Mlph/MyoVA tripartite complex, which links melanosomes to the peripheral actin network, is required to achieve melanosome transfer to surrounding keratinocytes in the epidermis. Here we report a novel homozygous missense mutation c.127G>A, p.G43S in exon 2 of the RAB27A gene of an Afghani GSII patient. Laser scanning confocal microscopy showed that the G43S mutation, which is located in the highly conserved switch I region of Rab27A, induces perinuclear localization of melanosomes in normal melanocytes, and fails to restore melanosomes to the actin-rich periphery in GSII melanocytes. Co-immunoprecipitation studies showed that Rab27A(G43S) fails to interact with its effector Melanophilin, indicating that the switch I region functions in the recruitment of Rab effector proteins.
Westbroek
Wendy
W
Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. wwestbro@mail.nih.gov
Tuchman
Maya
M
Tinloy
Bradford
B
De Wever
Olivier
O
Vilboux
Thierry
T
Hertz
Jens M
JM
Hasle
Henrik
H
Heilmann
Carsten
C
Helip-Wooley
Amanda
A
Kleta
Robert
R
Gahl
William A
WA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000346:Afghanistan; D020816:Amino Acid Motifs; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000737:chemistry / Q000378:metabolism; D020460:Melanosomes / Q000737:chemistry / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D016415:Sequence Alignment; D013577:Syndrome; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; C492410:MLPH protein, human; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins