Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment

Abstract

Background Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy. Objective To define a genetic syndrome of severe atopy, elevated serum IgE, immune deficiency, autoimmunity, and motor and neurocognitive impairment. Methods Eight patients from two families who had similar syndromic features were studied. Thorough clinical evaluations, including brain MRI and sensory evoked potentials, were performed. Peripheral lymphocyte flow cytometry, antibody responses, and T cell cytokine production were measured. Whole exome sequencing was performed to identify disease-causing mutations. Immunoblotting, qRT-PCR, enzymatic assays, nucleotide sugar and sugar phosphate analyses along with MALDI-TOF mass spectrometry of glycans were used to determine the molecular consequences of the mutations. Results Marked atopy and autoimmunity were associated with increased TH2 and TH17 cytokine production by CD4+ T cells. Bacterial and viral infection susceptibility were noted along with T cell lymphopenia, particularly of CD8+ T cells, and reduced memory B cells. Apparent brain hypomyelination resulted in markedly delayed evoked potentials and likely contributed to neurological abnormalities. Disease segregated with novel autosomal recessive mutations in a single gene, phosphoglucomutase 3 (PGM3). Although PGM3 protein expression was variably diminished, impaired function was demonstrated by decreased enzyme activity and reduced UDP-GlcNAc, along with decreased O- and N-linked protein glycosylation in patients’ cells. These results define a new Congenital Disorder of Glycosylation. Conclusions Autosomal recessive, hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability and hypomyelination.

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

“…In addition to the human IPEX syndrome, dysregulated Th2 responses, atopy, and elevated IgE levels occur in a range of primary human immunodeficiencies, some of which are phenocopied in the corresponding mouse models (13)(14)(15)(16)(17)(18). The variety of genes that are affected in these disorders -e.g., STAT3, DOCK8, PGM3 and multiple genes involved in TCR signaling such as LAT, ZAP70, or RAG -suggests that hyper IgE phenotypes can result from alterations in a number of distinct immunological pathways.…”

Genomics of Immune Diseases and New Therapies

“…In the realm of immune disease, the phenotype often relates to deficiencies in immune responses manifested by viral, bacterial, fungal, or parasitic infections (2, 8, 35, 36). Conversely, it can involve overactive immune responses leading to cellular or antibody-mediated autoimmunity or atopic disease such as asthma (37, 38). Immune homeostasis can also be deranged with the accumulation of immune cells and/or the distortion of immune subsets.…”

“…In current databases of Mendelian monogenic immune diseases, autosomal recessive (AR) disorders are 3–4 times more common than autosomal dominant (AD) diseases partly because they were the easiest to solve using classic approaches (25). Immunodeficiencies due to AR LOF mutations can be caused by homozygous alleles or two different LOF alleles (biallelic or compound heterozygous) (37, 38). In countries with high consanguinity, AR disorders involve LOF alleles that are usually homozygous.…”

“…Several recent examples show how gene identification has led directly to new therapeutic concepts for immune diseases. Identification in a group of patients with atopy, immunodeficiency, autoimmunity, and neurocognitive deficits of LOF mutations in phosphoglucomutase 3 (PGM3), which is an essential enzyme for the production of UDP-GlcNAc is one such example (38, 99, 100). How the defective protein glycosylation selectively alters immunity is unknown, but addition of GlcNAc to cells from the PGM3 patients restored intracellular UDP-GlcNAc levels (38).…”

Síndrome hiper-IgE. Lecciones de la función y defectos de STAT-3 o DOCK-8

“…Los pacientes con fenotipo similar al síndrome hiper-IgE muestran atopia, elevación de IgE, alteraciones neurológicas y del desarrollo. 44,45 …”