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

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 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. 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.

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

“…Previous animal research has suggested that certain clinical manifestations of MPS IIIB may be partially caused by overactivation of the TLR-4 cascade [ 17 ], largely driven by the PAMP/DAMP recognition of GAGs, such as heparan sulfate. Other studies have suggested that this pathophysiology may be relevant to different MPS types [ 6 , 7 , 8 , 9 ], with clinical studies implicating TNF-α as a prognostic value in MPS [ 10 ] and perhaps even a therapeutic target [ 24 , 25 ]. It is worth noting that a study of TLR4-KO-MPS-IIIB mice showed cytokine levels similar to wild type until after three months of age [ 9 ]; however, these mice eventually developed abnormal oxidative stress, putatively leading to neurodegeneration independent of innate inflammatory pathways.…”

“…Heparan sulfate and other GAGs have been shown to stimulate Toll-like Receptor 4 (TLR-4) in human dendritic cells [ 4 , 5 ], resulting in the production of many cellular cytokines, such as TNF-α, that mediate neuroinflammation and abnormal bone ossification due to enhanced chondrocyte turnover [ 6 , 7 , 8 , 9 ]. In MPS I, II, and VI, a high TNF-α was shown to be associated with increased disability and pain [ 10 ]. It is also speculated that vitamin D deficiency plays a key role in osteological manifestations of MPS [ 11 ].…”

Identification of key genes for hypertrophic cardiomyopathy using integrated network analysis of differential lncRNA and gene expression

“…CCDC154 is mainly involved in osteopetrosis and hypoplastic left heart syndrome ( 37 , 38 ), and CLCN7 is mainly involved in osteopetrosis and angiogenesis ( 39 ). Diseases associated with GNPTG include mucolipidosis III gamma and mucolipidosis ( 40 , 41 ), and those associated with PERCC1 include diarrhea 11, malabsorptive, congenital, and hepatocellular carcinoma ( 42 – 44 ). UNKL is associated with mucolipidosis ( 45 ), while the function and role of C16orf91 have not been reported.…”

CNS Manifestations in Mucolipidosis Type II—A Retrospective Analysis of Longitudinal Data on Neurocognitive Development and Neuroimaging in Eleven Patients

“…The latter comprise severe growth inhibition, skull, spine, thoracic and long tubular bone deformities, hip dysplasia, clubfeet, and joint contractures [ 3 , 4 , 5 , 6 , 7 ]. In addition to the somatic disease burden, MLII patients present with mental disabilities [ 3 , 4 , 8 ] and an intelligence quotient of below 85 [ 9 ]. MLII is regularly listed among lysosomal storage disorders associated with neurodegeneration and cognitive decline [ 3 , 8 , 10 , 11 , 12 , 13 ].…”

“…In addition to the somatic disease burden, MLII patients present with mental disabilities [ 3 , 4 , 8 ] and an intelligence quotient of below 85 [ 9 ]. MLII is regularly listed among lysosomal storage disorders associated with neurodegeneration and cognitive decline [ 3 , 8 , 10 , 11 , 12 , 13 ]. A recently published systematic review confirmed an early fatal outcome with a median age of death of 1.8 years [ 4 ], usually due to cardiopulmonary complications.…”