1. Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations
- Author
-
Maria Veiga-da-Cunha, Aline Vincent, Jérémie Rosain, Martin Castelle, Jill Serre, Laurent Renesme, Valérie Cormier-Daire, Takfarinas Kentache, Benjamin Fournier, Sophie Blesson, Nathalie Aladjidi, Despina Moshous, Mathieu Fusaro, Eulalie Lasseaux, Capucine Picard, Fanny Morice Picard, Nathalie Seta, Bénédicte Neven, Anne-Lise Delezoide, Catherine Fallet-Bianco, Emile Van Schaftingen, and UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique
- Subjects
Male ,0301 basic medicine ,Immunology ,Limb Deformities, Congenital ,macromolecular substances ,Disease ,Virus ,N-Acetylphosphoglucosamine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Missense mutation ,Congenital disorders of glycosylation ,Abnormalities, Multiple ,Bone Diseases, Developmental ,Severe combined immunodeficiency ,Primary immunodeficiency ,business.industry ,Infant, Newborn ,Infant ,Phosphoglucomutase 3 ,medicine.disease ,PGM3 ,030104 developmental biology ,Phosphoglucomutase ,Dysplasia ,Child, Preschool ,Face ,Skeletal dysplasia ,Female ,Severe Combined Immunodeficiency ,Nervous System Diseases ,business ,Congenital disorder of glycosylation ,030215 immunology - 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.
- Published
- 2021
- Full Text
- View/download PDF