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

TitlePGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.
Publication TypeJournal Article
Year of Publication2014
AuthorsStray-Pedersen, A, Backe, PH, Sorte, HS, Mørkrid, L, Chokshi, NY, Erichsen, HChristian, Gambin, T, Elgstøen, KBP, Bjørås, M, Wlodarski, MW, Krüger, M, Jhangiani, SN, Muzny, DM, Patel, A, Raymond, KM, Sasa, GS, Krance, RA, Martinez, CA, Abraham, SM, Speckmann, C, Ehl, S, Hall, P, Forbes, LR, Merckoll, E, Westvik, J, Nishimura, G, Rustad, CF, Abrahamsen, TG, Rønnestad, A, Osnes, LT, Egeland, T, Rødningen, OK, Beck, CR, Boerwinkle, E, Gibbs, RA, Lupski, JR, Orange, JS, Lausch, E, I Hanson, C
Corporate AuthorsBaylor-Johns Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2014 Jul 03
KeywordsBone Diseases, Developmental, Congenital Disorders of Glycosylation, Female, Humans, Immunologic Deficiency Syndromes, Male, Mutation, Pedigree, Phosphoglucomutase

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.

Alternate JournalAm J Hum Genet
PubMed ID24931394
PubMed Central IDPMC4085583
Grant ListU54HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States

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