Abstract
PurposePathogenic 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.MethodsWe analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgkoand 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.ResultsThe 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.ConclusionThe 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.
Highlights
Bone-forming osteoblasts and bone-resorbing osteoclasts coordinate continuous bone matrix remodeling that is required for healthy and functional bone maintenance
Bone remodeling is impaired in patients with MLIII alpha/beta but not with MLIII gamma
Genetic discerning two forms of MLIII as nonallelic clinical entities had to await the molecular characterization of the GlcNAc-1-phosphotransferase complex followed by the identification of the genes GNPTAB and GNPTG encoding its composing proteins [7, 8]
Summary
Bone-forming osteoblasts and bone-resorbing osteoclasts coordinate continuous bone matrix remodeling that is required for healthy and functional bone maintenance. The less progressive diseases MLIII alpha/beta (MIM 252600) and MLIII gamma (MIM 252605) are associated with specific biallelic missense variants in GNPTAB and all known biallelic variants in GNPTG, respectively, each of them being associated with residual GlcNAc-1-phosphotransferase activity [10]. A comprehensive analysis of patients, who were genetically diagnosed and classified as MLII, MLIII alpha/beta or MLIII gamma revealed that pathogenic variants in GNPTAB but not GNPTG result in increased bone resorption. Consistent with this observation, undecalcified histology and bone-specific histomorphometry in Gnptgko mice showed no impaired skeletal remodeling phenotype. We clearly demonstrate a gene-specific impact on bone remodeling abnormalities in human individuals and in mice, suggesting distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells
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