Novel 47.5-kb Deletion in RAB27A Results in Severe Griscelli Syndrome Type 2

Overview

Journal Mol Genet Metab

Specialty Endocrinology

Date 2010 Jul 2

PMID 20591709

Citations 6

Authors

Lisa M Vincent

Fred Gilbert

Jennifer I DiPace

Carla Ciccone

Thomas C Markello

Andrew Jeong

Heidi Dorward

Wendy Westbroek

William A Gahl

James B Bussel

Marjan Huizing

Affiliations

Soon will be listed here.

Abstract

Griscelli syndrome (GS), a rare autosomal recessive disorder characterized by partial albinism and immunological impairment and/or severe neurological impairment, results from mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes. We identified a Hispanic patient born of a consanguineous union who presented with immunodeficiency, partial albinism, hepatic dysfunction, hemophagocytosis, neurological impairment, nystagmus, and silvery hair indicative of Griscelli Syndrome Type 2 (GS2). We screened for point mutations, but only exons 2-6 of the patient's DNA could be PCR-amplified. Whole genome analysis using the Illumina 1M-Duo DNA Analysis BeadChip identified a homozygous deletion in the patient's DNA. The exact breakpoints of the 47.5-kb deletion were identified as chr15q15-q21.1: g.53332432_53379990del (NCBI Build 37.1); the patient lacks the promoter and 5'UTR regions of RAB27A, thus confirming the diagnosis of GS2.

Citing Articles

Griscelli Syndrome Type 2: Comprehensive Analysis of 149 New and Previously Described Patients with RAB27A Deficiency.

Maimaris J, Roa-Bautista A, Sohail M, Booth C, Cugno C, Chenchara L J Clin Immunol. 2024; 45(1):50.

PMID: 39607447 PMC: 11604824. DOI: 10.1007/s10875-024-01842-2.

A RAB27A 5' untranslated region structural variant associated with late-onset hemophagocytic lymphohistiocytosis and normal pigmentation.

Tesi B, Rascon J, Chiang S, Burnyte B, Lofstedt A, Fasth A J Allergy Clin Immunol. 2018; 142(1):317-321.e8.

PMID: 29522846 PMC: 6034010. DOI: 10.1016/j.jaci.2018.02.031.

Mapping of Id locus for dermal shank melanin in a Chinese indigenous chicken breed.

Xu J, Lin S, Gao X, Nie Q, Luo Q, Zhang X J Genet. 2018; 96(6):977-983.

PMID: 29321357 DOI: 10.1007/s12041-017-0862-z.

High resolution copy number variation data in the NCI-60 cancer cell lines from whole genome microarrays accessible through CellMiner.

Varma S, Pommier Y, Sunshine M, Weinstein J, Reinhold W PLoS One. 2014; 9(3):e92047.

PMID: 24670534 PMC: 3966786. DOI: 10.1371/journal.pone.0092047.

Identification of a novel SBF2 missense mutation associated with a rare case of thrombocytopenia using whole-exome sequencing.

Abuzenadah A, Zaher G, Dallol A, Damanhouri G, Chaudhary A, Al-Sayes F J Thromb Thrombolysis. 2013; 36(4):501-6.

PMID: 23334996 DOI: 10.1007/s11239-012-0864-x.

References

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

Gazit R, Aker M, Elboim M, Achdout H, Katz G, Wolf D . NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome. Blood. 2007; 109(10):4306-12. DOI: 10.1182/blood-2006-09-047159. View

Meeths M, Bryceson Y, Rudd E, Zheng C, Wood S, Ramme K . Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2009; 54(4):563-72. DOI: 10.1002/pbc.22357. View

Pereira-Leal J, Seabra M . The mammalian Rab family of small GTPases: definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the Ras superfamily. J Mol Biol. 2000; 301(4):1077-87. DOI: 10.1006/jmbi.2000.4010. View

Tolmachova T, Ramalho J, Anant J, Schultz R, Huxley C, Seabra M . Cloning, mapping and characterization of the human RAB27A gene. Gene. 1999; 239(1):109-16. DOI: 10.1016/s0378-1119(99)00371-6. View

Sanal O, Ersoy F, Tezcan I, Metin A, Yel L, Menasche G . Griscelli disease: genotype-phenotype correlation in an array of clinical heterogeneity. J Clin Immunol. 2002; 22(4):237-43. DOI: 10.1023/a:1016045026204. View

Henter J, Horne A, Arico M, Egeler R, Filipovich A, Imashuku S . HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2006; 48(2):124-31. DOI: 10.1002/pbc.21039. View

Kornreich R, Bishop D, Desnick R . Alpha-galactosidase A gene rearrangements causing Fabry disease. Identification of short direct repeats at breakpoints in an Alu-rich gene. J Biol Chem. 1990; 265(16):9319-26. View

Myerowitz R, Hogikyan N . A deletion involving Alu sequences in the beta-hexosaminidase alpha-chain gene of French Canadians with Tay-Sachs disease. J Biol Chem. 1987; 262(32):15396-9. View

10.

Hu X, Ray P, Worton R . Mechanisms of tandem duplication in the Duchenne muscular dystrophy gene include both homologous and nonhomologous intrachromosomal recombination. EMBO J. 1991; 10(9):2471-7. PMC: 452943. DOI: 10.1002/j.1460-2075.1991.tb07786.x. View

11.

Griscelli C, Durandy A, Daguillard F, Herzog C, Prunieras M . A syndrome associating partial albinism and immunodeficiency. Am J Med. 1978; 65(4):691-702. DOI: 10.1016/0002-9343(78)90858-6. View

12.

Meschede I, Santos T, Izidoro-Toledo T, Gurgel-Gianetti J, Espreafico E . Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure. Braz J Med Biol Res. 2008; 41(10):839-48. DOI: 10.1590/s0100-879x2008001000002. View

13.

Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S . Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000; 25(2):173-6. DOI: 10.1038/76024. View

14.

Zur Stadt U, Beutel K, Kolberg S, Schneppenheim R, Kabisch H, Janka G . Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat. 2005; 27(1):62-8. DOI: 10.1002/humu.20274. View

15.

Mamishi S, Modarressi M, Pourakbari B, Tamizifar B, Mahjoub F, Fahimzad A . Analysis of RAB27A gene in griscelli syndrome type 2: novel mutations including a deletion hotspot. J Clin Immunol. 2008; 28(4):384-9. DOI: 10.1007/s10875-008-9192-5. View

16.

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

17.

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

18.

Schuster F, Stachel D, Schmid I, Baumeister F, Graubner U, Weiss M . Griscelli syndrome: report of the first peripheral blood stem cell transplant and the role of mutations in the RAB27A gene as an indication for BMT. Bone Marrow Transplant. 2001; 28(4):409-12. DOI: 10.1038/sj.bmt.1703114. View

19.

Hume A, Collinson L, Rapak A, Gomes A, Hopkins C, Seabra M . Rab27a regulates the peripheral distribution of melanosomes in melanocytes. J Cell Biol. 2001; 152(4):795-808. PMC: 2195786. DOI: 10.1083/jcb.152.4.795. View

20.

Seabra M, Mules E, Hume A . Rab GTPases, intracellular traffic and disease. Trends Mol Med. 2002; 8(1):23-30. DOI: 10.1016/s1471-4914(01)02227-4. View