1. Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III
- Author
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Julian Stürznickel, Fernanda Sperb-Ludwig, Carolina Araujo Moreno, Giorgia Di Lorenzo, Ida Vanessa Doederlein Schwartz, Timur A. Yorgan, Tim N. Board, Dominic Winter, Sandra Breyer, Louise Lapagesse de Camargo Pinto, Nataniel Floriano Ludwig, Shiva Ahmadi, Luise Ammer, Thomas Renné, Renata Voltolini Velho, Sandra Pohl, Anne Foster, Tatyana Danyukova, Kerstin Kutsche, Tim Rolvien, Michaela Schweizer, Michael Amling, Dévora N Randon, Jean Mercer, Anke Baranowsky, Lena Marie Westermann, Thomas Braulke, Karen Tylee, Nicole Muschol, Thorsten Schinke, Elham Pourbarkhordariesfandabadi, and Denise P. Cavalcanti
- Subjects
0301 basic medicine ,Mucolipidosis ,Alpha (ethology) ,Transferases (Other Substituted Phosphate Groups) ,030209 endocrinology & metabolism ,Histology ,Biology ,medicine.disease ,GNPTG ,Molecular biology ,Bone resorption ,Article ,Bone remodeling ,03 medical and health sciences ,Mice ,030104 developmental biology ,0302 clinical medicine ,Mucolipidoses ,Bone cell ,medicine ,Animals ,Humans ,Bone Resorption ,Beta (finance) ,Genetics (clinical) - Abstract
Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.
- Published
- 2021