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Am J Hum Genet. 2014 Jul 3;95(1):96-107. doi: 10.1016/j.ajhg.2014.05.007. Epub 2014 Jun 12.

PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.

Author information

1
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.
2
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.
3
Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
4
Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
5
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.
6
Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
8
Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway.
9
Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
10
Department of Pediatrics, Freiburg University Hospital, 79106 Freiburg, Germany.
11
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.
12
Medical Genetics Laboratories, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
13
Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, MN 55905, USA.
14
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.
15
Pediatric Hematology Oncology, University of New Mexico, Albuquerque, NM 87106, USA.
16
Emory Genetics Laboratory, Department of Human Genetics, Emory University, Decatur, GA 30033, USA.
17
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.
18
Department of Radiology, Oslo University Hospital, 0424 Oslo, Norway.
19
Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8561, Japan.
20
Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Pediatrics, Oslo University Hospital, 0424 Oslo, Norway.
21
Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.
22
Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway; Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.
23
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.
24
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.

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.

PMID:
24931394
PMCID:
PMC4085583
DOI:
10.1016/j.ajhg.2014.05.007
[Indexed for MEDLINE]
Free PMC Article

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