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

Asbjørg Stray-Pedersen, Paul H. Backe, Hanne S. Sorte, Lars Mørkrid, Niti Y. Chokshi, Hans Christian Erichsen, Tomasz Gambin, Katja B.P. Elgstøen, Magnar Bjørås, Marcin W. Wlodarski, Marcus Krüger, Shalini N. Jhangiani, Donna M. Muzny, Ankita Patel, Kimiyo M. Raymond, Ghadir S. Sasa, Robert A. Krance, Caridad A. Martinez, Shirley M. Abraham, Carsten SpeckmannStephan Ehl, Patricia Hall, Lisa R. Forbes, Else Merckoll, Jostein Westvik, Gen Nishimura, Cecilie F. Rustad, Tore G. Abrahamsen, Arild Rønnestad, Liv T. Osnes, Torstein Egeland, Olaug K. Rødningen, Christine R. Beck, Eric A. Boerwinkle, Richard A. Gibbs, James R. Lupski, Jordan S. Orange, Ekkehart Lausch, I. Celine Hanson

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


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.

Original languageEnglish
Pages (from-to)96-107
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - 3 Jul 2014
Externally publishedYes


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