Novel mutations in the a3 subunit of vacuolar H+-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis

Michigami, Toshimi; Kageyama, Takashi; Satomura, Kenichi; Shima, Masasuke; Yamaoka, Kanji; Nakayama, Masahiro; Ozono, K

doi:10.1016/s8756-3282(01)00684-6

Cited by 42 publications

(48 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, mutations in the TCIRG1 gene, which encodes for the human a3 subunit, have been reported in patients affected by infantile malignant osteopetrosis, a heterogeneous autosomal recessive disorder of bone metabolism (12)(13)(14)(15). In addition, recent study has shown that V 0 subunit d2 is important for osteoclast fusion (37).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, mutations in the human TCIRG1 gene, which encodes for a osteoclast specific V-ATPase subunit, a3, results in infantile malignant osteopetrosis, thus substantiating the importance of V-ATPase in osteoclastic bone resorption (12)(13)(14)(15). The structural and functional analyses of the V-ATPase complex in osteoclasts might facilitate the development of anti-resorptive agents targeting specifically the osteoclast V-ATPases (16).…”

mentioning

confidence: 97%

See 1 more Smart Citation

Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone Resorption

Feng

Cheng

Pavlos

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Solubilization of mineralized bone by osteoclasts is largely dependent on the acidification of the extracellular resorption lacuna driven by the vacuolar (H؉)-ATPases (V-ATPases)polarized within the ruffled border membranes. V-ATPases consist of two functionally and structurally distinct domains, V 1 and V 0 . The peripheral cytoplasmically oriented V 1 domain drives ATP hydrolysis, which necessitates the translocation of protons across the integral membrane bound V 0 domain. Here, we demonstrate that an accessory subunit, Ac45, interacts with the V 0 domain and contributes to the vacuolar type proton pump-mediated function in osteoclasts. Consistent with its role in intracellular acidification, Ac45 was found to be localized to the ruffled border region of polarized resorbing osteoclasts and enriched in pH-dependent endosomal compartments that polarized to the ruffled border region of actively resorbing osteoclasts. Interestingly, truncation of the 26-amino acid residue cytoplasmic tail of Ac45, which encodes an autonomous internalization signal, was found to impair bone resorption in vitro. Furthermore, biochemical analysis revealed that although both wild type Ac45 and mutant were capable of associating with subunits a3, c, c؆, and d, deletion of the cytoplasmic tail altered its binding proximity with a3, c؆, and d. In all, our data suggest that the cytoplasmic terminus of Ac45 contains elements necessary for its proper interaction with V 0 domain and efficient osteoclastic bone resorption.Osteoclasts are terminally differentiated multinucleated cells derived from the hematopoietic lineage that specialize in the solubilization of mineralized bone material (1). Upon attachment to the bone surface, the osteoclast undergoes a series of cytoskeletal reorganization and polarization events that culminate in the formation of a unique apical membrane known as the ruffled border. The ruffled border is the "resorptive organelle" of the osteoclast and is formed by the polarized targeting and fusion of acidified intracellular vesicles with the plasma membrane (2-4). These transport vesicles courier acidifying machineries as well as osteolytic enzymes such as, TRACP, cathepsin K, and matrix metalloproteinases (2, 5-7) to the ruffled border membrane domain where each cargo plays a discrete role in the resorptive function. Vacuolar H ϩ -adenosine triphosphatases (V-ATPases) 5 that line the ruffled border have long been established to play a vital role in the resorptive process. V-ATPases function to pump H ϩ into the underlying resorptive lacunae. This elevation in protons results in a highly acidified microenvironment that solubilizes the mineralized component of bone while providing optimal conditions for the degradation of the exposed organic phase by collagenolytic enzymes such cathepsin K (2, 7).The importance of V-ATPase in osteoclastic bone resorption is exemplified by studies employing specific inhibitors and gene knock-out strategies to impair V-ATPase functions (8 -11). Furthermore, mutations in the human TCIRG1 g...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone Resorption

Feng

Cheng

Pavlos

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…After obtaining the informed consent by his parents, mutational analysis was performed by direct sequencing of all 20 exons of the TCIRG1 gene that encodes the a3 subunit of the vacuolar proton-ATPase, as previously reported (Michigami et al 2002). TCIRG1 is important for the resorptive function of osteoclasts.…”

Section: Case Presentationmentioning

confidence: 99%

“…Mutations in at least 10 genes have been identified as causative in humans, accounting for more than 70% of all IMO cases (Askmyr et al 2008). We had reported one of these mutations previously (Michigami et al 2002).…”

Section: Introductionmentioning

confidence: 96%

A Fatal Case of Infantile Malignant Osteopetrosis Complicated by Pulmonary Arterial Hypertension after Hematopoietic Stem Cell Transplantation

Kuroyanagi

Kawasaki

Noda

et al. 2014

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H + -ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two-nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT.

show abstract

“…In the 50% of cases (Fig. 1), the disease is due to mutations in TCIRG1 (Frattini et al 2000;Kornak et al 2000;Sobacchi et al 2001;Michigami et al 2002;Scimeca et al 2003;Susani et al 2004;Souraty et al 2007) which encodes for the osteoclast-specific a3 subunit of the proton pump responsible for the acidification of the resorption lacuna leading to bone resorption. Patients bearing mutations in this gene display a classical, homogeneous osteopetrotic phenotype and respond well to HSCT, when a suitable donor is available.…”

Section: Treating Human Aro: the Osteoclast-rich Formsmentioning

confidence: 99%

Prognostic potential of precise molecular diagnosis of Autosomal Recessive Osteopetrosis with respect to the outcome of bone marrow transplantation

et al. 2008

View full text Add to dashboard Cite

Hematopoietic stem cell transplantation (HSCT) is often the only practical approach to fatal genetic defects. One of the first pathologies which HSCT was applied to was Autosomal Recessive Osteopetrosis (ARO), a rare genetic bone disease in which a deficit in bone resorption by osteoclasts leads to increased bone density and secondary defects. The disease is often lethal early in life unless treated with HSCT. In utero transplantation (IUT) of the oc/oc mouse, reproducing the clinical features of a subset of ARO, has demonstrated that the quality of life and the survival of transplanted animals are greatly improved, suggesting that a similar protocol could be applied to humans. However, recently the dissection of the molecular bases of the disease has shown that ARO is genetically heterogeneous and has revealed the presence of subsets of patients which do not benefit from HSCT. This observation highlights the importance of molecular diagnosing ARO to identify and establish the proper therapies for a better prognosis. In particular, on the basis of experimental results in murine models, efforts should be undertaken to develop approaches such as IUT and new pharmacological strategies.

show abstract

Novel mutations in the a3 subunit of vacuolar H+-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis

Cited by 42 publications

References 17 publications

Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone Resorption

Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone Resorption

A Fatal Case of Infantile Malignant Osteopetrosis Complicated by Pulmonary Arterial Hypertension after Hematopoietic Stem Cell Transplantation

Prognostic potential of precise molecular diagnosis of Autosomal Recessive Osteopetrosis with respect to the outcome of bone marrow transplantation

Contact Info

Product

Resources

About