Elsevier

Molecular Immunology

Volume 90, October 2017, Pages 57-63
Molecular Immunology

A founder mutation underlies a severe form of phosphoglutamase 3 (PGM3) deficiency in Tunisian patients

https://doi.org/10.1016/j.molimm.2017.06.248Get rights and content

Highlights

  • Identification of a recurrent mutation in PGM3 gene in Tunisian patients.

  • Glu340 del mutation in PGM3 gene is associated with a severe clinical phenotype.

  • The first founder mutation in PGM3 gene is herein reported.

Abstract

Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Mutations in PGM3 gene have been recently shown to underlie a new congenital disorder of glycosylation often associated to elevated IgE. Herein, we report twelve PGM3 deficient patients. They belong to three highly consanguineous families, originating from a rural district in the west central Tunisia. The patient’s clinical phenotype is characterized by severe respiratory and cutaneous infections as well as developmental delay and severe mental retardation. Fourteen patients died in early infancy before diagnosis supporting the severity of the clinical phenotype.

Laboratory findings revealed elevated IgE, CD4 lymphopenia and impaired T cell proliferation in most patients. Genetic analysis showed the presence, of a unique homozygous mutation (p.Glu340del) in PGM3 gene leading to reduced PGM3 abundance. Segregating analysis using fifteen polymorphic markers overlapping PGM3 gene showed that all patients inherited a common homozygous haplotype encompassing 10-Mb on chromosome 6. The founder mutational event was estimated to have occurred approximately 100 years ago.

To date, (p.Glu340del) mutation represents the first founder mutation identified in PGM3 gene. These findings will facilitate the development of preventive approaches through genetic counselling and prenatal diagnosis in the affected families.

Introduction

Phosphoglutamase 3 (PGM3) deficiency, a congenital disorder of glycosylation (PGM3-CDG), is caused by hypomorphic mutations in PGM3 gene. PGM3 protein, previously known as N-acetylglucosamine-phosphate mutase (AGM1), catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) into N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P). The latter is required for the synthesis of Uridine Diphosphate N-Acetylglucosamine (UDP-GlcNAc), an important precursor for protein glycosylation (Freeze, 2013, Greig et al., 2007, Jaeken, 2012, Li et al., 2000, Pang et al., 2002). Indeed, UDP-GlcNAc is essential for N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis and O-GlcNAc modification (Greig et al., 2007). Glycosylation defects have been associated with different immune disorders frequently showing neurologic impairment (Jaeken and Carchon, 2004, Scott et al., 2014). The lack of Pgm3 is lethal in mice while hypomorphic and null alleles cause developmental and hematological defects (Greig et al., 2007).

In a previous study, we revealed that PGM3 gene, segregated with the disease and followed a recessive mode of inheritance in two consanguineous Tunisian families with HIES-like phenotype. These patients had in addition a psychomotor retardation and developmental delay (Sassi et al., 2014). We identified two mutations that affect highly conserved amino acid residues, one substitution (p.Leu83Ser) and a single amino acid deletion (p.Glu340del). The latter, located in the sugar-binding domain of PGM3, blocks the formation of bi-antennary N-glycans and is associated with the most severe pathology as well as reduced PGM3 abundance (Sassi et al., 2014). Our results were supported by the study of Zhang et al., reporting three other PGM3 mutations in eight patients presenting the same clinical phenotype (Zhang et al., 2014). Interestingly, Stray-Pedersen et al. reported three other PGM3 deficient patients with the classical features of congenital disorder of glycosylation (CGD), but with a severe combined immune deficiency (SCID). Only one patient had elevated IgE levels (Stray-Pedersen et al., 2014). Thus, PGM3 deficiency can be associated with a broad variety of symptoms which is not always associated with elevated serum IgE levels.

Almost all PGM3 homozygous mutations have been identified in consanguineous families. All these families originated from the Middle East and the North African region (Tunisia, Morocco, Turkey, Egypt and Afghanistan) characterized by a high rate of consanguinity reaching 50% in some areas (Barbouche et al., 2011).

Herein, we report the first founder mutation in PGM3 gene (p.Glu340del) in twelve Tunisian patients belonging to three consanguineous families originating from a rural district in west central Tunisia. Furthermore, we provide evidence that this mutation arose from a recent common ancestor.

Section snippets

Patients

Twelve Tunisian patients were investigated and underwent clinical examination. They originated from the same rural area of the governorate of Kasserine located in west central Tunisia. Blood samples were collected for immunological and genetic investigation. Informed consent was obtained. A detailed history of all family members was obtained by personal interviews and pedigrees were constructed.

Proliferation assays

Peripheral blood mononuclear cells (PBMCs) (2 × 105 cells/well in 200 μl medium) were plated in

Clinical features of PGM3 deficient patients

We included in the present study twelve patients (six males and six females) belonging to three unrelated consanguineous kindreds (A, B and C) originating from the same rural location (Fig. 1). Most of them presented with the clinical triad of recurrent pneumonia, recurrent skin abscesses, and a highly increased serum IgE levels. They also developed a neurological impairment with variable severity. Patients 1, 2 and 3, belonging to family A have been previously described (Sassi et al., 2014)

Discussion

PGM3 deficiency is a multisystem disorder characterized by the clinical features of congenital disorder of glycosylation (CDG) frequently associated with elevated serum IgE levels. A total of nine either homozygous or compound heterozygous PGM3 mutations have been identified in twenty-four patients. These patients have different clinical and immunological phenotypes which can vary in severity from mild cases to severe dependent on the type and location of the mutation (Lundin et al., 2015,

Conclusion

In summary, we herein report the first founder mutation in PGM3 gene. We also provide evidence that this mutation arises from a recent common ancestor 100 years ago. These findings will facilitate the implementation of a preventive approach through genetic counselling and prenatal diagnosis in affected families.

Conflicts of interest

None of the authors has any potential financial conflict of interest related to this manuscript.

Acknowledgements

We would like to thank the patients and their families for their kind cooperation. We thank Beya Largueche for technical assistance and Nebil Belhadjhmida for field work. This work was supported by the Tunisian Ministry of Higher Education, Research and Technology (LR11IPT02).

References (20)

There are more references available in the full text version of this article.

Cited by (26)

  • ERBIN and phosphoglucomutase 3 deficiency

    2023, Current Opinion in Immunology
  • Inborn errors of IL-6 family cytokine responses

    2021, Current Opinion in Immunology
    Citation Excerpt :

    In comparison with STAT3-HIES patients, there are fewer extra-hematopoietic manifestations. Patients with biallelic loss-of-function variants in phosphoglucomutase 3 (PGM3), present with an AR disorder including several features of classical HIES including increased serum IgE levels, recurrent skin and pulmonary infections, abscesses and bronchiectasis [38–40]. This can be partially explained by defective glycosylation of GP130 in theses patients causing lower GP130 surface expression and impaired STAT3 activation [41] (Figure 2).

  • Common presentations and diagnostic approaches

    2020, Stiehm's Immune Deficiencies: Inborn Errors of Immunity
  • Primary immune deficiencies associated with a Th2 diathesis

    2020, Stiehm's Immune Deficiencies: Inborn Errors of Immunity
View all citing articles on Scopus
View full text