Journal ArticleDOI
Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.
Annalisa Frattini,Paul J. Orchard,Cristina Sobacchi,Silvia Giliani,Mario Abinun,Jan P. Mattsson,David J. Keeling,Ann Katrin Andersson,Pia Wallbrandt,Luigi Zecca,Luigi D. Notarangelo,Paolo Vezzoni,Anna Villa +12 more
TLDR
It is shown that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis, indicating that mutations in TC IRG1 are a frequent cause of autosomal recessive osteopeterosis in humans.Abstract:
Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis, the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts, which suggests that the defect directly interferes with osteoclast differentiation. In other mutants, it is the function of the osteoclast that seems to be affected, as they show normal or elevated numbers of non-functioning osteoclasts. Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.read more
Citations
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Journal ArticleDOI
Genetic regulation of osteoclast development and function
TL;DR: The past five years have witnessed important insights into osteoclast formation and function and many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.
Journal ArticleDOI
Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology.
TL;DR: The acidity of intracellular compartments and the extracellular environment is crucial to various cellular processes, including membrane trafficking, protein degradation, bone resorption and sperm maturation, and the V-ATPases represent attractive and potentially highly specific drug targets.
Journal ArticleDOI
A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.
Randall D. Little,John P. Carulli,Richard G. Del Mastro,Josée Dupuis,Mark Osborne,Colleen Folz,Susan P. Manning,Pamela Marie Swain,Shan Chuan Zhao,Brenda K. Eustace,Michelle M. Lappe,Lia Spitzer,Susan Zweier,Karen Braunschweiger,Youssef Benchekroun,Xintong Hu,Ronald Adair,Linda Chee,Michael Fitzgerald,Craig Tulig,Anthony Caruso,Nia Tzellas,Alicia Bawa,Barbara Franklin,Shannon M. McGuire,Shannon M. McGuire,Xavier Nogués,Xavier Nogués,Gordon Gong,Kristina Allen,Anthony Anisowicz,Arturo Morales,Peter T. Lomedico,Susan M. Recker,Paul Van Eerdewegh,Robert R. Recker,Mark L. Johnson +36 more
TL;DR: It is suggested that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.
Journal ArticleDOI
Molecular Structure and Physiological Function of Chloride Channels
TL;DR: The loss of distinct Cl- channels leads to an impairment of transepithelial transport in cystic fibrosis and Bartter's syndrome, to increased muscle excitability in myotonia congenita, to reduced endosomal acidification and impaired endocytosis in Dent's disease, and to impaired extracellular acidification by osteoclasts and osteopetrosis.
Journal ArticleDOI
The molecular understanding of osteoclast differentiation.
TL;DR: The RANKL signaling pathway has promise as a strategy for suppressing the excessive osteoclast formation characteristic of a variety of bone diseases and is controlled by an epigenetic mechanism, which has profound implications for the general mechanism of irreversible cell fate determination.
References
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OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis
Young-Yun Kong,Hiroki Yoshida,Ildiko Sarosi,Hong-Lin Tan,Emma Timms,Casey Capparelli,Sean Morony,Antonio J. Oliveira-dos-Santos,Gwyneth Van,Annick Itie,Wilson Khoo,Andrew Wakeham,Colin R. Dunstan,David L. Lacey,Tak W. Mak,William J. Boyle,Josef M. Penninger +16 more
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Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice
TL;DR: It is demonstrated that src is not required for general cell viability (possibly because of functional overlap with other tyrosine kinases related to src) and an essential role for src in bone formation is uncovered.
Journal ArticleDOI
Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice
Paul Saftig,Ernst Hunziker,Olaf Wehmeyer,Sheila J. Jones,Alan Boyde,Winfried Rommerskirch,Jörg Detlev Moritz,Peter Schu,Kurt von Figura +8 more
TL;DR: Assaying the resorptive activity of cathepsin-K-deficient osteoclasts in vitro revealed this function to be severely impaired, which supports the contention that cathepsypsin K is of major importance in bone remodeling.
Journal ArticleDOI
Osteoclastic bone resorption by a polarized vacuolar proton pump
Harry C. Blair,Steven L. Teitelbaum,Steven L. Teitelbaum,Robert W. Ghiselli,Stephen L. Gluck +4 more
TL;DR: The mechanism by which osteoclasts transport protons into that resorptive microenvironment was identified by means of adenosine triphosphate-dependent weak base accumulation in isolated osteoclast membrane vesicles, which exhibited substrate and inhibition properties characteristic of the vacuolar, electrogenic H+-transporting H-ATPase.
Journal ArticleDOI
Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).
Paolo Macchi,Anna Villa,Silvia Giliani,Maria Grazia Sacco,Annalisa Frattini,Fulvio Porta,A. G. Ugazio,J A Johnston,Fabio Candotti,John J. O'Shea +9 more
TL;DR: Two unrelated T- B+SCID patients who have homozygous mutations in the gene for Jak-3 are investigated and abnormalities in the Jak/STAT signalling pathway can account for SCID in humans.