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

Ben-Khemis, Leila; Mekki, Najla; Ben‐Mustapha, Imen; Rouault, Karen; Mellouli, Fethi; Khémiri, M.; Béjaoui, Mohamed; Essaddam, L.; Ben-Becher, Saayda; Boughamoura, Lamia; Hassayoun, S.; Ben-Ali, Meriem; Barbouche, Mohamed‐Ridha

doi:10.1016/j.molimm.2017.06.248

Cited by 31 publications

(35 citation statements)

References 19 publications

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“…It is well known that distribution of PIDs with more than 1 mode of transmission is often different in consanguineous populations as compared to outbred ones. Indeed, in our settings, the AR mode of inheritance accounted for most kindreds with chronic granulomatous disease, 49 hyper-IgM syndrome, 50 and hyper-IgE syndrome 51 unlike what is reported in European, American, and Asian series and/or registries. 2 The identification of this novel form of ALPS raises the possibility to revisit the molecular basis and the classification of ALPS-FAS ( Fig.…”

Section: Novel Form Of Ar Alps-fas With Normal or Residual Protein Excontrasting

confidence: 65%

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Ben‐Mustapha

Agrebi

Barbouche

2017

Journal of Leukocyte Biology

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Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.

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Section: Novel Form Of Ar Alps-fas With Normal or Residual Protein Excontrasting

confidence: 65%

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Ben‐Mustapha

Agrebi

Barbouche

2017

Journal of Leukocyte Biology

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“…The encoded protein mediates the interconversion of GlcNAc‐6‐P into GlcNAc‐1‐P, critical for the synthesis of UDP‐GlcNAc. PGM3‐CDG (MIM: 615816) is an immunodeficiency disorder characterized by recurrent bacterial and fungal infections, often associated with increased levels of IgE . IgE glycosylation was assessed in two patients but no significant differences with controls were found .…”

Section: The Immunological Impact Of Glycosylation Defects—an Update mentioning

confidence: 99%

CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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Glycosylation is an essential biological process that adds structural and functional diversity to cells and molecules, participating in physiological processes such as immunity. The immune response is driven and modulated by protein‐attached glycans that mediate cell‐cell interactions, pathogen recognition and cell activation. Therefore, abnormal glycosylation can be associated with deranged immune responses. Within human diseases presenting immunological defects are congenital disorders of glycosylation (CDG), a family of around 130 rare and complex genetic diseases. In this review, we have identified 23 CDG with immunological involvement, characterized by an increased propensity to—often life‐threatening—infection. Inflammatory and autoimmune complications were found in 7 CDG types. CDG natural history(ies) and the mechanisms behind the immunological anomalies are still poorly understood. However, in some cases, alterations in pathogen recognition and intracellular signaling (eg, TGF‐β1, NFAT, and NF‐κB) have been suggested. Targeted therapies to restore immune defects are only available for PGM3‐CDG and SLC35C1‐CDG. Fostering research on glycoimmunology may elucidate the involved pathophysiological mechanisms and open new therapeutic avenues, thus improving CDG patients' quality of life.

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“…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.…”

Section: Pgm3 Deficiencymentioning

confidence: 99%

Human hyper-IgE syndrome: singular or plural?

et al. 2018

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Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50 years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

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

Cited by 31 publications

References 19 publications

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

CDG and immune response: From bedside to bench and back

Human hyper-IgE syndrome: singular or plural?

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