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Case Reports
. 2015 Dec;161(2):366-72.
doi: 10.1016/j.clim.2015.10.002. Epub 2015 Oct 19.

Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene

Karin E Lundin  1 , Abdulrahman Hamasy  2 , Paul Hoff Backe  3 , Lotte N Moens  4 , Elin Falk-Sörqvist  4 , Katja B Elgstøen  5 , Lars Mørkrid  5 , Magnar Bjørås  6 , Carl Granert  7 , Anna-Carin Norlin  8 , Mats Nilsson  9 , Birger Christensson  10 , Stephan Stenmark  11 , C I Edvard Smith  12
Affiliations
Case Reports

Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene

Karin E Lundin et al. Clin Immunol. 2015 Dec.

Abstract

Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.

Keywords: CDG; Congenital defects of glycosylation; N-acetylglucosamine-phosphate mutase; Primary immunodeficiency; hyper-IgE syndrome.

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Figures

Fig. 1
Fig. 1
Identified mutation in the patient and her relatives. A) Sequencing results identifying the mutation in the PGM3 gene, which demonstrates the exchange of amino acid 322 from Ile to Thr. B) Pedigree chart showing the presence of the identified mutation. The arrow indicates the proband. The mutation could not be verified in two of the immunodeficient deceased siblings due to lack of biological samples. Neither has the presence of the mutation been studied in any of the grandchildren, who all are healthy. One child of the proband died at birth due to an intrauterine infection.
Fig. 2
Fig. 2
Human PGM3-model and enzyme activity. The molecular model of the human PGM3 based on the X-ray structure of Pgm3 from Aspergillus fumigatus. The position of the Ile322Thr mutation is indicated in red. It is located at the end of the β-sheet in the sugar-binding domain (domain 3) and seems to be engaged in hydrophobic contacts that likely contribute to the stability of the domain. The Ile322Thr substitution might therefore have a destabilizing effect on the three-dimensional structure of the protein. The green sphere represents the central magnesium ion. The effect of the amino acid substitutions on PGM3 was tested by mass spectrometry in “multiple reaction monitoring” mode; the transition from the molecular ion (m/z 300) to a fragment specific to the substrate (GlcNAc-6-P) (m/z 138) was used for measuring substrate consumption in relation to that of the wild-type. Mean of 3 experiments, SEM in parenthesis.
Fig. 3
Fig. 3
Stability of PGM3 protein in EBV-transformed cells: Whole cell lysates from EBV-transformed cells derived from a healthy control without mutation in the PGM3 gene (control), a control with one mutated allele (M.D.), and the patient with homozygous mutations (A.D.) were processed for Western blotting. Actin serves as control of the loading. Proteins were detected using rabbit polyclonal anti-PGM3, and mouse monoclonal anti-Actin antibodies. Panel A shows the filter from a representative experiment. Panel B shows the mean of relative intensities for PGM3 expression from four different experiments with error bars representing standard deviation of the mean. Statistical significance was analyzed using a one-way ANOVA followed by Duncan comparison test. *P ≤ 0.01, **P ≤ 0.001.
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