Erschienen in:
03.02.2021 | Original Article
Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations
verfasst von:
Mathieu Fusaro, Aline Vincent, Martin Castelle, Jérémie Rosain, Benjamin Fournier, Maria Veiga-da-Cunha, Takfarinas Kentache, Jill Serre, Catherine Fallet-Bianco, Anne-Lise Delezoide, Laurent Renesme, Fanny Morice Picard, Eulalie Lasseaux, Nathalie Aladjidi, Nathalie Seta, Valérie Cormier-Daire, Emile van Schaftingen, Bénédicte Neven, Despina Moshous, Sophie Blesson, Capucine Picard
Erschienen in:
Journal of Clinical Immunology
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Ausgabe 5/2021
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Abstract
Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein–Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.