title: PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.
abstract: Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA; Section of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: strayped@bcm.edu.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Backe
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Hanne S
authors.initials: HS
authors.lastname: Sorte
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Mørkrid
authors.affiliation: Section of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Niti Y
authors.initials: NY
authors.lastname: Chokshi
authors.affiliation: Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Erichsen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Katja B P
authors.initials: KB
authors.lastname: Elgstøen
authors.affiliation: Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Department of Pediatrics, Freiburg University Hospital, 79106 Freiburg, Germany.
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.affiliation: Department of Pediatrics, Freiburg University Hospital, 79106 Freiburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Medical Genetics Laboratories, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, MN 55905, USA.
authors.forename: Kimiyo M
authors.initials: KM
authors.lastname: Raymond
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy and Texas Children's Cancer and Hematology Centers, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Ghadir S
authors.initials: GS
authors.lastname: Sasa
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy and Texas Children's Cancer and Hematology Centers, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy and Texas Children's Cancer and Hematology Centers, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Caridad A
authors.initials: CA
authors.lastname: Martinez
authors.affiliation: Pediatric Hematology Oncology, University of New Mexico, Albuquerque, NM 87106, USA.
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Abraham
authors.affiliation: Department of Pediatrics, Freiburg University Hospital, 79106 Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Department of Pediatrics, Freiburg University Hospital, 79106 Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Emory Genetics Laboratory, Department of Human Genetics, Emory University, Decatur, GA 30033, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hall
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA; Section of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Forbes
authors.affiliation: Department of Radiology, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Else
authors.initials: E
authors.lastname: Merckoll
authors.affiliation: Department of Radiology, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Jostein
authors.initials: J
authors.lastname: Westvik
authors.affiliation: Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8561, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Cecilie F
authors.initials: CF
authors.lastname: Rustad
authors.affiliation: Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Tore G
authors.initials: TG
authors.lastname: Abrahamsen
authors.affiliation: Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Arild
authors.initials: A
authors.lastname: Rønnestad
authors.affiliation: Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Liv T
authors.initials: LT
authors.lastname: Osnes
authors.affiliation: Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Torstein
authors.initials: T
authors.lastname: Egeland
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Olaug K
authors.initials: OK
authors.lastname: Rødningen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Medical Genetics Laboratories, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jlupski@bcm.tmc.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA; Section of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Department of Pediatrics, Freiburg University Hospital, 79106 Freiburg, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.affiliation: Section of Immunology, Allergy, and Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: I Celine
authors.initials: IC
authors.lastname: Hanson
mesh_terms: D001848:Bone Diseases, Developmental / Q000235:genetics*; D018981:Congenital Disorders of Glycosylation / Q000235:genetics*; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010733:Phosphoglucomutase / Q000235:genetics*
chemical_list: C549916:PGM3 protein, human; D010733:Phosphoglucomutase