Congenital disorders of glycosylation and intellectual disability

Wolfe, Lynne A.; Krasnewich, Donna M.

doi:10.1002/ddrr.1115

Cited by 26 publications

(19 citation statements)

References 80 publications

(167 reference statements)

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“…The other recent report on PGM3-deficiency based on a study of eight patients from two unrelated families described similar clinical features as well as renal and hepatic abnormalities [8]. A very consistent feature in patients identified with PGM3 mutations was the presence of developmental delay and psychomotor retardation, which is in agreement with previous findings in patients with glycosylation defects [75]. In addition, some patients with PGM3 mutations have connective tissue and skeletal abnormalities, including joint hyperextensibility, scoliosis and characteristic facies, similarly to the case in AD-HIES caused by STAT3 mutations [8,9].…”

Section: Clinical Phenotype Of Ar-hies/pgm3 Deficiencysupporting

confidence: 87%

Primary Immunodeficiencies with Elevated IgE

Mogensen¹

2015

International Reviews of Immunology

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In recent years a number of primary immunodeficiencies (PIDs) characterized by elevated Immunoglobulin E (IgE) levels have been uncovered and termed as Hyper-IgE syndrome (HIES). In addition to the elevated levels of IgE, patients with these PIDs display a spectrum of infections by staphylococci and fungi, and in some cases viruses, particularly affecting skin and lungs. Most of these PIDs also have a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities. The genetic basis for the majority of conditions with elevated IgE has now been established and includes mutations in STAT3, DOCK8, TYK2, and most recently PGM3 molecules. However, in some patients with the relevant phenotype, mutations in these molecules are not identified, suggesting additional genetic etiologies of HIES not yet discovered. As the immunological and molecular basis of HIES is being unraveled, important insights are emerging that may have implications for our understanding of basic principles of immunology and protective immunity as well as for the pathogenesis and clinical management of patients with these complex and challenging PIDs. In this review, are presented the current knowledge on the clinical presentation, infectious phenotype, and the genetic and immunological pathogenesis of hyper-IgE syndromes as well as some other PIDs with elevated levels of IgE.

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Section: Clinical Phenotype Of Ar-hies/pgm3 Deficiencysupporting

confidence: 87%

Primary Immunodeficiencies with Elevated IgE

Mogensen¹

2015

International Reviews of Immunology

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“…[4]. The glycosylation of nascent proteins modifies their physical properties, increasing their stability and directing their folding and quality control in the ER [5,6].…”

Section: Introductionmentioning

confidence: 99%

DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress

et al. 2017

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Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates. UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway. The aim of the present study was to examine the effect of six variants in DPAGT1 detected in patients with DPAGT1-CDG, and the role of endoplasmic reticulum stress, as part of the search for therapeutic strategies to use against DPAGT1-CDG. The effect of the six mutations, i.e., c.358C>A (p.Leu120Met), c.791T>G (p.Val264Gly), c.901C>T (p.Arg301Cys), c.902G>A (p.Arg301His), c.1154T>G (p.Leu385Arg), and of the novel mutation c.329T>C (p.Phe110Ser), were examined via the analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. In addition, the transient expression of different mutations was analysed in COS-7 cells. The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane. The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG. Even so, the fibroblasts of patients with DPAGT1-CDG seemed to be more sensitive to the stressor tunicamycin. The present work improves our knowledge of DPAGT1-CDG and provides bases for developing tailored splicing and folding therapies.

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“…The neurologic features are evocative of other glycosylation defects, such as DPAGT1-CDG (CDG Ij) and MOGS-CDG (CDG-IIb), which are both associated with primary hypomyelination. These overlaps in three distinct glycosylation disorders indicate an important role for glycosylation in normal axonal health 13 .…”

Section: Discussionmentioning

confidence: 99%

“…Typical features of CDG are extremely broad, but can include motor and neurologic deficits, hematologic abnormalities, dysmorphism, and other malformations. Abnormal immune function has been observed, including hypogammaglobulinemia with decreased B cell numbers in ALG12-CDG (also called CDG-Ig) due to mutations in ALG12 11 , leukocyte adhesion deficiency type 2 or SLC35C1-CDG due to mutations in SLC35C1 (also called CDG-IIc) 12 , glucosidase I deficiency MOGS-CDG or CDG-IIb 13 . The widespread clinical manifestations are thought to be due to the ubiquity of glycosylation and its central roles in an array of normal cellular functions.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang¹,

Yu²,

Ichikawa³

et al. 2014

Journal of Allergy and Clinical Immunology

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201

216

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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.

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Congenital disorders of glycosylation and intellectual disability

Cited by 26 publications

References 80 publications

Primary Immunodeficiencies with Elevated IgE

Primary Immunodeficiencies with Elevated IgE

DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress

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

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