ArticleThe Journal of biological chemistry2012
Osteopetrosis mutation R444L causes endoplasmic reticulum retention and misprocessing of vacuolar H+-ATPase a3 subunit.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.Communications biology · 2023Pooled it
- Spectrum and functions of ion channels and transporters in osteoclasts.Bone research · 2026Review
- The V-ATPaseInternational journal of molecular sciences · 2021Review
- Gold Nanomaterials and Bone/Cartilage Tissue Engineering: Biomedical Applications and Molecular Mechanisms.Frontiers in chemistry · 2021Review
- Regulation and function of V-ATPases in physiology and disease.Biochimica et biophysica acta. Biomembranes · 2020Review
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases.Translational neurodegeneration · 2020Review
- Lysosomal dysfunction in proteinopathic neurodegenerative disorders: possible therapeutic roles of cAMP and zinc.Molecular brain · 2019Review
- Chemical probes and drug leads from advances in synthetic planning and methodology.Nature reviews. Drug discovery · 2018Review
- Molecular mechanisms of cutis laxa- and distal renal tubular acidosis-causing mutations in V-ATPaseThe Journal of biological chemistry · 2018Article
- V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis.Theranostics · 2018Review
- Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease.Ageing research reviews · 2016Review
- Article
- Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification.Cell reports · 2015Article
- Discovery of a Small-Molecule Probe for V-ATPase Function.Journal of the American Chemical Society · 2015Article
- Glycoprotein folding and quality-control mechanisms in protein-folding diseases.Disease models & mechanisms · 2014Review
- Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime.Biochemical Society transactions · 2013Review
- The role of autophagy in neurodegenerative disease.Nature medicine · 2013Review
- Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification.The European journal of neuroscience · 2013Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Osteopetrosis is a genetic bone disease characterized by increased bone density and fragility. The R444L missense mutation in the human V-ATPase a3 subunit (TCIRG1) is one of several known mutations in a3 and other proteins that can cause this disease. The autosomal recessive R444L mutation results in a particularly malignant form of infantile osteopetrosis that is lethal in infancy, or early childhood. We have studied this mutation using the pMSCV retroviral vector system to integrate the cDNA construct for green fluorescent protein (GFP)-fused a3(R445L) mutant protein into the RAW 264.7 mouse osteoclast differentiation model. In comparison with wild-type a3, the mutant glycoprotein localized to the ER instead of lysosomes and its oligosaccharide moiety was misprocessed, suggesting inability of the core-glycosylated glycoprotein to traffic to the Golgi. Reduced steady-state expression of the mutant protein, in comparison with wild type, suggested that the former was being degraded, likely through the endoplasmic reticulum-associated degradation pathway. In differentiated osteoclasts, a3(R445L) was found to degrade at an increased rate over the course of osteoclastogenesis. Limited proteolysis studies suggested that the R445L mutation alters mouse a3 protein conformation. Together, these data suggest that Arg-445 plays a role in protein folding, or stability, and that infantile malignant osteopetrosis caused by the R444L mutation in the human V-ATPase a3 subunit is another member of the growing class of protein folding diseases. This may have implications for early-intervention treatment, using protein rescue strategies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.