title: Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome.
abstract: The hereditary stomatocytoses are a series of dominantly inherited hemolytic anemias in which the permeability of the erythrocyte membrane to monovalent cations is pathologically increased. The causative mutations for some forms of hereditary stomatocytosis have been found in the transporter protein genes, RHAG and SLC4A1. Glucose transporter 1 (glut1) deficiency syndromes (glut1DSs) result from mutations in SLC2A1, encoding glut1. Glut1 is the main glucose transporter in the mammalian blood-brain barrier, and glut1DSs are manifested by an array of neurologic symptoms. We have previously reported 2 cases of stomatin-deficient cryohydrocytosis (sdCHC), a rare form of stomatocytosis associated with a cold-induced cation leak, hemolytic anemia, and hepatosplenomegaly but also with cataracts, seizures, mental retardation, and movement disorder. We now show that sdCHC is associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak, as shown by expression studies in Xenopus oocytes. On the basis of a 3-dimensional model of glut1, we propose potential mechanisms underlying the phenotypes of the 2 mutations found. We investigated the loss of stomatin during erythropoiesis and find this occurs during reticulocyte maturation and involves endocytosis. The molecular basis of the glut1DS, paroxysmal exercise-induced dyskinesia, and sdCHC phenotypes are compared and discussed.
authors.affiliation: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, United Kingdom.
authors.forename: Joanna F
authors.initials: JF
authors.lastname: Flatt
authors.forename: Hélène
authors.initials: H
authors.lastname: Guizouarn
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Burton
authors.forename: Franck
authors.initials: F
authors.lastname: Borgese
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Tomlinson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Forsyth
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Baldwin
authors.forename: Bari E
authors.initials: BE
authors.lastname: Levinson
authors.forename: Philippe
authors.initials: P
authors.lastname: Quittet
authors.forename: Patricia
authors.initials: P
authors.lastname: Aguilar-Martinez
authors.forename: Jean
authors.initials: J
authors.lastname: Delaunay
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stewart
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Bruce
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002386:Cataract / Q000097:blood / Q000235:genetics; D003847:Deoxyglucose / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D051272:Glucose Transporter Type 1 / Q000097:blood / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D017136:Ion Transport; D008565:Membrane Proteins / Q000097:blood / Q000172:deficiency*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D013577:Syndrome; D014982:Xenopus laevis
chemical_list: D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D050505:Mutant Proteins; D011994:Recombinant Proteins; C495677:SLC2A1 protein, human; C036860:STOM protein, human; D003847:Deoxyglucose