title: Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency.
abstract: Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c --> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.
authors.affiliation: Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12, 0NN, UK.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Almeida
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: D Mark
authors.initials: DM
authors.lastname: Layton
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Sellick
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeda
authors.forename: Stephen
authors.initials: S
authors.lastname: Richards
authors.forename: Scott
authors.initials: S
authors.lastname: Patterson
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kotsianidis
authors.forename: Luigina
authors.initials: L
authors.lastname: Mollica
authors.forename: Dorothy H
authors.initials: DH
authors.lastname: Crawford
authors.forename: Alastair
authors.initials: A
authors.lastname: Baker
authors.forename: Michael
authors.initials: M
authors.lastname: Ferguson
authors.forename: Irene
authors.initials: I
authors.lastname: Roberts
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005260:Female; D005808:Genes, Recessive; D017261:Glycosylphosphatidylinositols / Q000172:deficiency*; D006456:Hemoglobinuria / Q000235:genetics; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D012640:Seizures / Q000235:genetics; D013927:Thrombosis / Q000235:genetics
chemical_list: D017261:Glycosylphosphatidylinositols; D008364:Mannosyltransferases; C486036:PIGM protein, human