title: Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility.
abstract: The Rab GTPase Rab27B and one of its effector proteins, Slac2-b (also known as EXPH5, exophilin-5), have putative roles in intracellular vesicle trafficking but their relevance to human disease is not known. By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited skin fragility born to consanguineous Iraqi parents. All three individuals harbor the mutation c.5786delC (p.Pro1929Leufs(∗)8) in EXPH5, which truncates the 1,989 amino acid Slac2-b protein by 52 residues. The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs. There was no increased bleeding tendency, no neurologic abnormalities, and no increased incidence of infection. Analysis of an affected person's skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles. A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes. Slac2-b was also shown to colocalize with Rab27B and β4 integrin to early adhesion initiation sites in spreading normal keratinocytes. Collectively, our findings identify an unexpected role for Slac2-b in inherited skin fragility and expand the clinical spectrum of human disorders of GTPase effector proteins.
authors.affiliation: St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK. john.mcgrath@kcl.ac.uk
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Stone
authors.forename: Rumena
authors.initials: R
authors.lastname: Begum
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.forename: Celine
authors.initials: C
authors.lastname: Pourreyron
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Anna E
authors.initials: AE
authors.lastname: Martinez
authors.forename: Jemima E
authors.initials: JE
authors.lastname: Mellerio
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D005260:Female; D018095:Germ-Line Mutation; D006201:Hair Diseases / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D010375:Pedigree; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C514892:EXPH5 protein, human; C512960:Rab27B protein, human; D020691:rab GTP-Binding Proteins