Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis

10.1038/77131 ◽  
2000 ◽  
Vol 25 (3) ◽  
pp. 343-346 ◽  
Author(s):  
Annalisa Frattini ◽  
Paul J. Orchard ◽  
Cristina Sobacchi ◽  
Silvia Giliani ◽  
Mario Abinun ◽  
...  
Keyword(s):  
Proton Pump ◽  
Autosomal Recessive ◽  
Vacuolar Proton Pump ◽  
Autosomal Recessive Osteopetrosis

scholarly journals Sibling Pair Linkage and Association Studies between Peak Bone Mineral Density and the Gene Locus for the Osteoclast-Specific Subunit (OC116) of the Vacuolar Proton Pump on Chromosome 11p12-13

2002 ◽  
Vol 87 (8) ◽  
pp. 3819-3824 ◽  
Author(s):  
Gwenaelle Carn ◽  
Daniel L. Koller ◽  
Munro Peacock ◽  
Siu L. Hui ◽  
Wayne E. Evans ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Neck ◽  
Bone Mineral ◽  
Proton Pump ◽  
Autosomal Recessive ◽  
Chromosomal Region ◽  
Mineral Density ◽  
Peak Bone Mineral Density ◽  
Peak Bmd ◽  
Vacuolar Proton Pump

A major determinant of the risk of osteoporosis is peak bone mineral density (BMD), which has been shown to have substantial heritability. The genes for 3 BMD-related phenotypes (autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessives osteopetrosis) are all in the chromosome 11q12-13 region. We reported linkage of peak BMD in a large sample of healthy premenopausal sister pairs to this same chromosomal region, suggesting that the genes underlying these 3 disorders may also play a role in determining peak BMD within the normal population. To test this hypothesis, we examined the gene responsible for 1 form of autosomal recessive osteopetrosis, TCIRG1, which encodes an osteoclast-specific subunit (OC116) of the vacuolar proton pump. We identified 3 variants in the sequence of TCIRG1, but only one, single nuclear polymorphism 906713, had sufficient heterozygosity for use in genetic analyses. Our findings were consistent with linkage to femoral neck BMD, but not to spine BMD, in a sample of 995 healthy premenopausal sister pairs. However, further analysis, using both population and family-based disequilibrium approaches, did not demonstrate any evidence of association between TCIRG1 and the spine or femoral neck BMD. Therefore, our linkage data suggest that the chromosomal region that contains OC116 harbors a gene that affects peak BMD, but our association results indicate that polymorphisms in the OC116 gene do not affect peak BMD.

scholarly journals Regulatory assembly of the vacuolar proton pump V o V 1 -ATPase in yeast cells by FLIM-FRET

2010 ◽  
Author(s):  
Stefan Ernst ◽  
Claire Batisse ◽  
Nawid Zarrabi ◽  
Bettina Böttcher ◽  
Michael Börsch
Keyword(s):  
Proton Pump ◽  
Yeast Cells ◽  
Vacuolar Proton Pump

The COOH termini of NBC3 and the 56-kDa H+-ATPase subunit are PDZ motifs involved in their interaction

2003 ◽  
Vol 284 (3) ◽  
pp. C667-C673 ◽  
Author(s):  
Alexander Pushkin ◽  
Natalia Abuladze ◽  
Debra Newman ◽  
Vladimir Muronets ◽  
Pejvak Sassani ◽  
...  
Keyword(s):  
Amino Acid ◽  
Proton Pump ◽  
Rat Kidney ◽  
Pdz Domain ◽  
Intercalated Cells ◽  
Regulatory Factor ◽  
Atpase Subunit ◽  
Sodium Bicarbonate Cotransporter ◽  
Terminal Amino ◽  
Vacuolar Proton Pump

The electroneutral sodium bicarbonate cotransporter 3 (NBC3) coimmunoprecipitates from renal lysates with the vacuolar H+-ATPase. In renal type A and B intercalated cells, NBC3 colocalizes with the vacuolar H+-ATPase. The involvement of the COOH termini of NBC3 and the 56-kDa subunit of the proton pump in the interaction of these proteins was investigated. The intact and modified COOH termini of NBC3 and the 56-kDa subunit of the proton pump were synthesized, coupled to Sepharose beads, and used to pull down kidney membrane proteins. Both the 56- and the 70-kDa subunits of the proton pump, as well as a PDZ domain containing protein Na+/H+ exchanger regulatory factor 1 (NHERF-1), were bound to the intact 18 amino acid NBC3 COOH terminus. A peptide truncated by five COOH-terminal amino acids did not bind these proteins. Replacement of the COOH-terminal leucine with glycine blocked binding of both the proton pump subunits but did not affect binding of NHERF-1. The 18 amino acid COOH terminus of the 56-kDa subunit of the proton pump bound NHERF-1 and NBC3, but the truncated and modified peptide did not. A complex of NBC3, the 56-kDa subunit of the proton pump, and NHERF-1 was identified in rat kidney. The data indicate that the COOH termini of NBC3 and the 56-kDa subunit of the vacuolar proton pump are PDZ-interacting motifs that are necessary for the interaction of these proteins. NHERF-1 is involved in the interaction of NBC3 and the vacuolar proton pump.

scholarly journals Malignant Autosomal Recessive Osteopetrosis Caused by Spontaneous Mutation of Murine Rank

2004 ◽  
Vol 19 (10) ◽  
pp. 1689-1697 ◽  
Author(s):  
Raj P Kapur ◽  
Zhenqiang Yao ◽  
Malissa HK Iida ◽  
Christine M Clarke ◽  
Barbara Doggett ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Spontaneous Mutation ◽  
Autosomal Recessive Osteopetrosis

scholarly journals R51Q SNX10 induces osteopetrosis by promoting uncontrolled fusion of monocytes to form giant, non-functional osteoclasts

2018 ◽  
Author(s):  
Maayan Barnea ◽  
Merle Stein ◽  
Sabina Winograd-Katz ◽  
Moran Shalev ◽  
Esther Arman ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Precursor Cell ◽  
Unique Combination ◽  
Sorting Nexin ◽  
Autosomal Recessive Osteopetrosis

SummaryThe molecular mechanisms that regulate fusion of monocytes into functional osteoclasts are virtually unknown. We describe a knock-in mouse model for the R51Q mutation in sorting nexin 10 (SNX10) that exhibits osteopetrosis and related symptoms of patients of autosomal recessive osteopetrosis linked to this mutation. Osteopetrosis arises in homozygous R51Q SNX10 mice due to a unique combination of reduced numbers of osteoclasts that are non-functional. Fusion of mutant monocytes is deregulated and occurs rapidly and continuously to form giant, non-functional osteoclasts. Mutant osteoclasts mature quickly and survive poorly in vitro, possibly accounting for their scarcity in vivo. These cells also exhibit impaired ruffled borders, which are required for bone resorption, providing an additional basis for the osteopetrotic phenotype. More broadly, we propose that the maximal size of osteoclasts is actively determined by a genetically-regulated, cell-autonomous mechanism that limits precursor cell fusion, and for which SNX10 is required.

scholarly journals Effects of inhibitors of the vacuolar proton pump on hepatic heterophagy and autophagy

2001 ◽  
Vol 1510 (1-2) ◽  
pp. 243-257 ◽  
Author(s):  
Seyed Ali Mousavi ◽  
Rune Kjeken ◽  
Trond Olav Berg ◽  
Per Ottar Seglen ◽  
Trond Berg ◽  
...  
Keyword(s):  
Proton Pump ◽  
Vacuolar Proton Pump

scholarly journals Association of the 16-kDa Subunit c of Vacuolar Proton Pump with the Ileal Na+-dependent Bile Acid Transporter

2004 ◽  
Vol 279 (16) ◽  
pp. 16295-16300 ◽  
Author(s):  
An-Qiang Sun ◽  
Natarajan Balasubramaniyan ◽  
Chuan-Ju Liu ◽  
Mohammad Shahid ◽  
Frederick J. Suchy
Keyword(s):  
Bile Acid ◽  
Proton Pump ◽  
Subunit C ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Vacuolar Proton Pump
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