title: Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding.
abstract: BACKGROUND
  Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and often fatal disorder characterized by defective cellular cytotoxicity and hyperinflammation, and the only cure known to date is hematopoietic stem cell transplantation. Mutations in RAB27A, LYST, and AP3B1 give rise to FHL associated with oculocutaneous albinism, and patients with FHL are usually only screened for mutations in these genes when albinism is observed. A number of patients with FHL and normal pigmentation remain without a genetic diagnosis.
  
  
  OBJECTIVE
  We asked whether patients with FHL with immunodeficiency but with normal pigmentation might sometimes have mutations that affected cellular cytotoxicity without affecting pigmentation.
  
  
  METHODS
  We carried out mutation analysis of RAB27A, LYST, and AP3B1 in patients with FHL with pigment dilution, as well as a cohort with no clinical evidence of pigment dilution but no mutations in the other known FHL-related genes (PRF1, STXBP2, and UNC13D).
  
  
  RESULTS
  We identify patients with Griscelli syndrome type 2 with biallelic mutations in RAB27A in the absence of albinism. All 6 patients carried mutations at amino acids R141, Y159, or S163 of Rab27a that disrupt the interaction of Rab27a with Munc13-4, without impairing the interaction between melanophilin and Rab27a.
  
  
  CONCLUSIONS
  These studies highlight the need for RAB27A sequencing in patients with FHL with normal pigmentation and identify a critical binding site for Munc13-4 on Rab27a, revealing the molecular basis of this interaction.
authors.affiliation: Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children's Hospital, Florence, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cetica
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hackmann
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Samantha
authors.initials: S
authors.lastname: Grieve
authors.affiliation: Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children's Hospital, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sieni
authors.affiliation: Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children's Hospital, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ciambotti
authors.affiliation: Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer Children's Hospital, Florence, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Coniglio
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.affiliation: Immunology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Romagnoli
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, United Kingdom. Electronic address: gg305@cam.ac.uk.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Griffiths
authors.affiliation: Pediatric Oncology Network, Istituto Toscano Tumori (I.T.T.), Florence, Italy. Electronic address: maurizio.arico@asp.rg.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000417:Albinism / Q000235:genetics; D016022:Case-Control Studies; D015550:Cell Degranulation; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003602:Cytotoxicity, Immunologic; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D054353:Perforin / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D012880:Skin Pigmentation / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; C492410:MLPH protein, human; D008565:Membrane Proteins; C507969:UNC13D protein, human; D000075745:rab27 GTP-Binding Proteins; D054353:Perforin; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins
keywords: Griscelli syndrome type 2; Hemophagocytic lymphohistiocytosis; cytotoxic T lymphocyte; familial hemophagocytic lymphohistiocytosis; melanophilin; natural killer cells