title: A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT.
abstract: To ascertain the genetic basis of a paroxysmal nocturnal hemoglobinuria (PNH) case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8-MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI anchor synthesis, whereas PIGT is essential for attachment of the preassembled GPI anchor to proteins. Although a single mutation event in the X-chromosomal gene PIGA is known to cause GPI-anchored protein deficiency, 2 such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany. peter.krawitz@gmail.com
authors.forename: Peter M
authors.initials: PM
authors.lastname: Krawitz
authors.forename: Britta
authors.initials: B
authors.lastname: Höchsmann
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Britta
authors.initials: B
authors.lastname: Teubner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Krüger
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoellein
authors.forename: Christina
authors.initials: C
authors.lastname: Schneider
authors.forename: Dmitri
authors.initials: D
authors.lastname: Parkhomchuk
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D016022:Case-Control Studies; D055028:Comparative Genomic Hybridization; D003412:Cricetulus; D005091:Exons / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D050172:Genes, X-Linked; D018095:Germ-Line Mutation / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D000217:Acyltransferases; C081007:COOH-terminal signal transamidase