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

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.

Human hyper-IgE syndrome: singular or plural?

“…We review here the history of HIES, and what is currently known about its three proposed genetic forms, and we discuss the contribution of the corresponding mouse models to studies of the pathogenesis of this disease. Like other investigators [14, 15], we suggest that the term “HIES” best applies to patients with a phenotype of AD STAT3 deficiency.…”

“…However, too few data are currently available to analyze the correlation of genotype with cellular and clinical phenotypes in patients. Surprisingly, measurements of residual PGM3 expression and function did not differentiate between the patients of these two cohorts [7-10, 14, 170, 171]. It would, nevertheless, be very interesting to compare the deleteriousness of biallelic PGM3 genotypes with that of various cellular, immunological, and clinical phenotypes.…”

A Novel PGM3 Mutation Is Associated With a Severe Phenotype of Bone Marrow Failure, Severe Combined Immunodeficiency, Skeletal Dysplasia, and Congenital Malformations

“…(9) Thus, a total of 23 patients from 11 families have been reported to have pathogenic PGM3 mutations. (1,2,4,8,9) Here we present two siblings with a skeletal dysplasia, severe combined immunodeficiency, bone marrow failure, renal malformations, and intestinal involvement, for whom we performed WES and found a new PGM3 mutation. We also compare the clinical features of our patients with the previously reported cases.…”

“…(1) The patient described by Lundin and colleagues presented eosinophilia and nearly normal to low values of neutrophils and T, B, and NK cells. (8) In mice carrying hypomorphic mutations in Pgm3, the anomalies included modest anemia and thrombocytopenia and severe reduction in B and T cells with an inverted CD4/CD8 ratio. (6) Stray-Pedersen and colleagues showed that hematopoietic stem cell transplant was efficient to cure the immune deficiency in 2 patients.…”

Biology, Mechanism, and Structure of Enzymes in the α- d -Phosphohexomutase Superfamily

“…PGM3 is an essential enzyme in the hexosamine biosynthetic pathway required for the production of UDP-GlcNAc (Willems, van Engelen, & Lefeber, 2016). Mutations in PGM3 were recently identified as causing an autosomal recessive immunodeficiency syndrome, combined with CDG phenotypic features (Lundin et al, 2015; Sassi et al, 2014; Stray-Pedersen et al, 2014; Zhang et al, 2014). As is the case with PGM1 deficiency, patient phenotypes in PGM3 deficiency are variable and complex.…”