Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis

Souraty, Noëlle; Noun, Peter; Djambas-Khayat, Claudia; Chouery, Éliane; Pangrazio, Alessandra; Villa, Anna; Lefranc, Gérard; Frattini, Annalisa; Mégarbané, André

doi:10.1016/j.ejmg.2007.01.005

Cited by 29 publications

(21 citation statements)

References 15 publications

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“…The phenotype of the patients with mutations in OSTM1 is very similar to that observed in other ARO patients, and thus it is severe and shows the classic osteopetrotic traits, such as very high BMD, absence of bone marrow cavities, hepatosplenomegaly and anemia (Chalhoub et al 2003;Maranda et al 2008;Quarello et al 2004;Ramirez et al 2004;Souraty et al 2007). Studies of cells from these patients are sparse; however, a recent case report indicated that osteoclasts in vitro are morphologically normal (Maranda et al 2008).…”

Section: Osteopetrosis-associated Transmembrane Proteinmentioning

confidence: 82%

Advances in osteoclast biology resulting from the study of osteopetrotic mutations

et al. 2008

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Osteopetrosis is the result of mutations affecting osteoclast function. Careful analyses of osteopetrosis have provided instrumental information on bone remodeling, including the coupling of bone formation to bone resorption. Based on a range of novel genetic mutations and the resulting osteoclast phenotypes, we discuss how osteopetrosis models have clarified the function of the coupling of bone formation to bone resorption, and the pivotal role of the osteoclast and their function in this phenomenon. We highlight the distinct possibility that osteoclast activities can be divided into two separate avenues: bone resorption and control of bone formation.

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Section: Osteopetrosis-associated Transmembrane Proteinmentioning

confidence: 82%

Advances in osteoclast biology resulting from the study of osteopetrotic mutations

et al. 2008

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“…The first well‐defined human OSTM1 osteopetrotic mutation resulted partially in an in‐frame deletion of exon 5 encoding the transmembrane region, indicating a key membrane‐associated role of OSTM1 . This is also supported by the majority of OSTM1 osteopetrotic nonsense or deletion mutations localized upstream of exon 5 . Expression in cell culture of the murine Ostm1 lacking transmembrane region can produce a secreted protein .…”

Section: Introductionmentioning

confidence: 94%

Ostm1 Bifunctional Roles in Osteoclast Maturation: Insights From a Mouse Model Mimicking a Human OSTM1 Mutation

Pata

Vacher

2018

Journal of Bone and Mineral Research

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Ostm1 mutations are responsible for the most severe form of osteopetrosis in human and mice. To gain insight into Ostm1 cellular functions, we engineered a conditional in-frame deletion of the Ostm1 transmembrane domain and generated the first Ostm1 mouse model with a human mutation. Systemic targeting of Ostm1 loss of transmembrane domain produced osteopetrosis, as in the null Ostm1 gl/gl mouse. Significantly, conditional osteoclast targeting of Ostm1 resulted in similar osteopetrosis, thereby demonstrating that the intrinsic Ostm1 osteoclast deficiency is solely responsible for the mouse phenotype. Our analysis showed oversized osteoclasts with enhanced multinucleation associated with stimulation of intracellular calcium levels, of Nfatc1 nuclear re-localization, and of specific downstream Nfatc1 target genes, providing compelling evidence that Ostm1 is a negative regulator of preosteoclast fusion. Moreover, mature OCs with Ostm1 loss of transmembrane domain show appropriate levels of intracellular acidification but an altered distribution pattern, highlighting misregulation of endolysosome localization and dispersion. Consistently, the hydrolases tartrate-resistant acid phosphatase (TRAP) and cathepsin K (Ctsk) normally produced are sequestered within the osteoclasts and are not extracellularly secreted. These studies defined bifunctional roles for Ostm1 as a major regulator of preosteoclast cytoskeletal rearrangements toward cell multinucleation and of mature osteoclast intracellular lysosomal trafficking and exocytosis mechanism, both of which are essential for bone resorption. Importantly, these Ostm1 molecular and regulatory functions could serve as preclinical targets in this mouse model toward osteoclastogenic pathologies as osteoporosis and inflammation-induced bone loss. © 2018 American Society for Bone and Mineral Research.

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“…Homozygosity for the TCIRG1 IVS14‐1 G > A mutation and others is well documented in multiple patients with ARIO without evidence of a particular genotype associated with anomalies observed in this case [Scimeca et al, 2003; Susani et al, 2004; Souraty et al, 2007]. However, TCIRG1 has two normal splice variants with confirmed protein products: TV1, which encodes the osteoclast proton pump, and TV2, which encodes a T‐cell inhibitory receptor and functions in regulating immune responses [Heinemann et al, 1999; Bulwin et al, 2006].…”

mentioning

confidence: 66%

A patient with TCIRG1‐related infantile osteopetrosis presenting with congenital anomalies: Chance association or a case for pleiotropy?

Conway

Falk

2007

American J of Med Genetics Pt A

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Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis

Cited by 29 publications

References 15 publications

Advances in osteoclast biology resulting from the study of osteopetrotic mutations

Advances in osteoclast biology resulting from the study of osteopetrotic mutations

Ostm1 Bifunctional Roles in Osteoclast Maturation: Insights From a Mouse Model Mimicking a Human OSTM1 Mutation

A patient with TCIRG1‐related infantile osteopetrosis presenting with congenital anomalies: Chance association or a case for pleiotropy?

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