Cellular and Clinical Report of New Griscelli Syndrome Type III Cases

Overview

Journal Pigment Cell Melanoma Res

Date 2011 Sep 3

PMID 21883982

Citations 9

Authors

Wendy Westbroek

Aharon Klar

Andrew R Cullinane

Shira G Ziegler

Haggit Hurvitz

Ashraf Ganem

Kirkland Wilson

Heidi Dorward

Marjan Huizing

Haled Tamimi

Igor Vainshtein

Yackov Berkun

Moran Lavie

William A Gahl

Yair Anikster

Affiliations

Soon will be listed here.

Abstract

The RAB27A/Melanophilin/Myosin-5a tripartite protein complex is required for capturing mature melanosomes in the peripheral actin network of melanocytes for subsequent transfer to keratinocytes. Mutations in any one member of this tripartite complex cause three forms of Griscelli syndrome (GS), each with distinct clinical features but with a similar cellular phenotype. To date, only one case of GS type III (GSIII), caused by mutations in the Melanophilin (MLPH) gene, has been reported. Here, we report seven new cases of GSIII in three distinct Arab pedigrees. All affected individuals carried a homozygous missense mutation (c.102C>T; p.R35W), located in the conserved Slp homology domain of MLPH, and had hypomelanosis of the skin and hair. We report the first cellular studies on GSIII melanocytes, which demonstrated that MLPH(R35W) causes perinuclear aggregation of melanosomes in melanocytes, typical for GS. Additionally, co-immunoprecipitation assays showed that MLPH(R35W) lost its interaction with RAB27A, indicating pathogenicity of the R35W mutation.

Citing Articles

Inhibition of Melanosome Transport by Inducing Exon Skipping in Melanophilin.

Kim J, Han S, Sung K, Seo J, Myung C, Jo C Biomol Ther (Seoul). 2023; 31(4):466-472.

PMID: 36971066 PMC: 10315340. DOI: 10.4062/biomolther.2022.167.

Griscelli syndrome type 1: a novel pathogenic variant, and review of literature.

Khorram E, Tabatabaiefar M, Yaghini O, Khorrami M, Yazdani V, Fakhr F Mol Genet Genomics. 2023; 298(2):485-493.

PMID: 36651988 DOI: 10.1007/s00438-022-01971-6.

Identification of a Novel Missense Mutation in a Chinese Griscelli Syndrome 3 Patient.

Huang Q, Yuan Y, Gong J, Zhang T, Qi Z, Yang X Front Med (Lausanne). 2022; 9:896943.

PMID: 35602484 PMC: 9120966. DOI: 10.3389/fmed.2022.896943.

Hair Shaft Examination: A Practical Tool to Diagnose Griscelli Syndrome.

Montero-Vilchez T, Remon-Love A, Tercedor-Sanchez J, Arias-Santiago S Dermatopathology (Basel). 2021; 8(1):49-53.

PMID: 33803120 PMC: 8008316. DOI: 10.3390/dermatopathology8010010.

Griscelli Syndrome Type 3 with Coexistent Universal Dyschromia-An Uncommon Association of a Rare Entity.

Mathachan S, Sinha S, Malhotra P Indian Dermatol Online J. 2020; 11(5):799-803.

PMID: 33235850 PMC: 7678511. DOI: 10.4103/idoj.IDOJ_572_19.

References

Kuroda T, Ariga H, Fukuda M . The actin-binding domain of Slac2-a/melanophilin is required for melanosome distribution in melanocytes. Mol Cell Biol. 2003; 23(15):5245-55. PMC: 165717. DOI: 10.1128/MCB.23.15.5245-5255.2003. View

Westbroek W, Lambert J, De Schepper S, Kleta R, Van Den Bossche K, Seabra M . Rab27b is up-regulated in human Griscelli syndrome type II melanocytes and linked to the actin cytoskeleton via exon F-Myosin Va transcripts. Pigment Cell Res. 2004; 17(5):498-505. DOI: 10.1111/j.1600-0749.2004.00173.x. View

Barral D, Ramalho J, Anders R, Hume A, Knapton H, Tolmachova T . Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome. J Clin Invest. 2002; 110(2):247-57. PMC: 151050. DOI: 10.1172/JCI15058. View

Raposo G, Marks M . Melanosomes--dark organelles enlighten endosomal membrane transport. Nat Rev Mol Cell Biol. 2007; 8(10):786-97. PMC: 2786984. DOI: 10.1038/nrm2258. View

Westbroek W, Lambert J, Bahadoran P, Busca R, Herteleer M, Smit N . Interactions of human Myosin Va isoforms, endogenously expressed in human melanocytes, are tightly regulated by the tail domain. J Invest Dermatol. 2003; 120(3):465-75. DOI: 10.1046/j.1523-1747.2003.12068.x. View

Hendrix A, Braems G, Bracke M, Seabra M, Gahl W, de Wever O . The secretory small GTPase Rab27B as a marker for breast cancer progression. Oncotarget. 2011; 1(4):304-308. PMC: 3058367. DOI: 10.18632/oncotarget.140. View

Westbroek W, Tuchman M, Tinloy B, de Wever O, Vilboux T, Hertz J . A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome. Mol Genet Metab. 2008; 94(2):248-54. PMC: 2430933. DOI: 10.1016/j.ymgme.2008.02.009. View

Hurvitz H, Gillis R, Klaus S, Klar A, Okon E . A kindred with Griscelli disease: spectrum of neurological involvement. Eur J Pediatr. 1993; 152(5):402-5. DOI: 10.1007/BF01955897. View

Stinchcombe J, Barral D, Mules E, Booth S, Hume A, Machesky L . Rab27a is required for regulated secretion in cytotoxic T lymphocytes. J Cell Biol. 2001; 152(4):825-34. PMC: 2195783. DOI: 10.1083/jcb.152.4.825. View

10.

Hume A, Ushakov D, Tarafder A, Ferenczi M, Seabra M . Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes. J Cell Sci. 2007; 120(Pt 17):3111-22. DOI: 10.1242/jcs.010207. View

11.

Strom M, Hume A, Tarafder A, Barkagianni E, Seabra M . A family of Rab27-binding proteins. Melanophilin links Rab27a and myosin Va function in melanosome transport. J Biol Chem. 2002; 277(28):25423-30. DOI: 10.1074/jbc.M202574200. View

12.

Wu X, Rao K, Zhang H, Wang F, Sellers J, Matesic L . Identification of an organelle receptor for myosin-Va. Nat Cell Biol. 2002; 4(4):271-8. DOI: 10.1038/ncb760. View

13.

Vaez M, Follett S, BedHom B, Gourichon D, Tixier-Boichard M, Burke T . A single point-mutation within the melanophilin gene causes the lavender plumage colour dilution phenotype in the chicken. BMC Genet. 2008; 9:7. PMC: 2253553. DOI: 10.1186/1471-2156-9-7. View

14.

Huizing M, Helip-Wooley A, Westbroek W, Gunay-Aygun M, Gahl W . Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet. 2008; 9:359-86. PMC: 2755194. DOI: 10.1146/annurev.genom.9.081307.164303. View

15.

Chen D, Guo J, Miki T, Tachibana M, Gahl W . Molecular cloning and characterization of rab27a and rab27b, novel human rab proteins shared by melanocytes and platelets. Biochem Mol Med. 1997; 60(1):27-37. DOI: 10.1006/bmme.1996.2559. View

16.

Kuroda T, Itoh T, Fukuda M . Functional analysis of slac2-a/melanophilin as a linker protein between Rab27A and myosin Va in melanosome transport. Methods Enzymol. 2006; 403:419-31. DOI: 10.1016/S0076-6879(05)03037-5. View

17.

Theos A, Truschel S, Raposo G, Marks M . The Silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Pigment Cell Res. 2005; 18(5):322-36. PMC: 2788625. DOI: 10.1111/j.1600-0749.2005.00269.x. View

18.

Wu X, Tsan G, Hammer 3rd J . Melanophilin and myosin Va track the microtubule plus end on EB1. J Cell Biol. 2005; 171(2):201-7. PMC: 2171176. DOI: 10.1083/jcb.200503028. View

19.

Van Gele M, Dynoodt P, Lambert J . Griscelli syndrome: a model system to study vesicular trafficking. Pigment Cell Melanoma Res. 2009; 22(3):268-82. DOI: 10.1111/j.1755-148X.2009.00558.x. View

20.

Hendrix A, Maynard D, Pauwels P, Braems G, Denys H, Van den Broecke R . Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. J Natl Cancer Inst. 2010; 102(12):866-80. PMC: 2886092. DOI: 10.1093/jnci/djq153. View