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

Abstract

Congenital disorders of glycosylation (CDGs) affect multiple systems and present a broad spectrum of clinical features, often including skeletal dysplasia. Exome sequencing has led to the identification of new CDG genes. Immune and skeletal phenotypes associated with mutations in PGM3, encoding a protein that converts N-acetyl-glucosamine-6-phosphate into N-acetyl-glucosamine-1-phosphate, were recently reported. Through exome sequencing, we identified a novel homozygous mutation (c.1135T>C; p.Phe379Leu) in PGM3 in two siblings with bone marrow failure, severe combined immunodeficiency, renal and intestinal malformations, and a skeletal dysplasia resembling Desbuquois dysplasia. Severe respiratory compromise secondary to lung hypoplasia and pulmonary hypertension, and intestinal obstruction led to their demise. We thus report the most severe phenotype described so far associated with PGM3 mutations. This CDG should be considered in the presence of skeletal dysplasia associated with severe immunodeficiency. © 2017 American Society for Bone and Mineral Research.

Sequence-structure relationships, expression profiles, and disease-associated mutations in the paralogs of phosphoglucomutase 1

“…Enzyme deficiencies of both PGM1 and PGM3 are associated with inherited disease in humans [ 9 – 14 ]. Currently, 18 residue positions in PGM1 and eight in PGM3 have established disease-related variants.…”

“…Moreover, previous evolutionary and expression analyses, which are key to an appreciation of their functional roles, preceded the dramatic increase of genomic and expression data. Finally, a better understanding of the human paralogs of PGM1 is timely, given the recent recognition of enzyme deficiencies of PGM1 and PGM3 as the cause of inherited diseases in humans [ 9 – 14 ]. PGM1 deficiency has features of both a glycogen storage disease and a congenital disorder of glycosylation, of types I and II.…”

Clinical Utility Gene Card for: PGM3 defective congenital disorder of glycosylation

“…At least thirty-eight genetically confirmed patients (from 16 families) have been reported [1][2][3][4][5][6][7][8][9]. The frequency and the prevalence of the disease are not known.…”

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

“…24 The discovery of patients with autosomal recessive hypomorphic mutations in Phosphoglucomutase 3 (PGM3) has provided us with the first example in humans of disrupted sugar metabolism resulting in severe allergic disease. [25][26][27][28][29][30][31] While null mutations in Pgm3 are incompatible with life, hypomorphic mutations generated in two mouse models result in an immunologic phenotype characterized by bone marrow failure. 23 Some human mutations likewise result in severe combined immunodeficiency (SCID) without evidence of atopy, [25][26][27] likely due in part to the lack of effector cells required for allergic inflammation.…”

“…[25][26][27][28][29][30][31] While null mutations in Pgm3 are incompatible with life, hypomorphic mutations generated in two mouse models result in an immunologic phenotype characterized by bone marrow failure. 23 Some human mutations likewise result in severe combined immunodeficiency (SCID) without evidence of atopy, [25][26][27] likely due in part to the lack of effector cells required for allergic inflammation. However, the majority of patients reported thus far with recessive PGM3 mutations present with marked elevations in IgE, severe atopic dermatitis, and virtually every clinical allergic process that has been described, including: immediate hypersensitivity to food and environmental allergens, food protein-induced enteroco- In mice, oral supplementation with GlcNAc increased intracellular UDP-GlcNAc pools and N-glycan branching, and was associated with increased growth and altered glucose homeostasis and lipid metabolism.…”