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Alessandra Pangrazio,
Anders Fasth,
Andrea Sbardellati,
Paul J Orchard,
Kimberly A Kasow,
Jamal Raza,
Canan Albayrak,
Davut Albayrak,
Olivier M Vanakker,
Barbara De Moerloose, [......],
Gabriele Strauss,
Jörn-Sven Kühl,
Elena Caldana, Nadia Lo Iacono,
Lucia Susani,
Uwe Kornak,
Ansgar Schulz,
Paolo Vezzoni,
Anna Villa,
Cristina Sobacchi
[show abstract]
[hide abstract]
ABSTRACT: Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than half of ARO cases. Afterwards, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the Sorting Nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in three consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in 3 cases of "Västerbottenian osteopetrosis", named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the RANKL, RANK and OSTM1-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by Hematopoietic Stem Cell Transplantation (HSCT). These results confirm the involvement of SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand SNX10 role in osteoclast physiology and verify whether this protein might be considered a new target for selective anti-resorptive therapies. © 2012 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2012; · 6.04 Impact Factor
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Nadia Lo Iacono,
Harry C Blair,
Pietro L Poliani,
Veronica Marrella,
Francesca Ficara,
Barbara Cassani,
Fabio Facchetti,
Elena Fontana,
Matteo M Guerrini,
Elisabetta Traggiai, [......],
Stefano Mantero,
Antonio Inforzato,
Serenella Valaperta,
Alessandra Pangrazio,
Laura Crisafulli,
Virginia Maina,
Paul Kostenuik,
Paolo Vezzoni,
Anna Villa,
Cristina Sobacchi
[show abstract]
[hide abstract]
ABSTRACT: In the last decades the molecular basis of monogenic diseases has been largely unraveled, whereas their treatment has often remained unsatisfactory. Autosomal recessive osteopetrosis (ARO) belongs to the small group of genetic diseases that are usually treated with hematopoietic stem cell transplantation (HSCT). However, this approach is not effective in the recently identified form carrying mutations in the RANKL gene. In this subset, therapy replacement approach based on RANKL delivery has a strong rationale. Here we demonstrate that the systematic administration of RANKL for 1 month to Rankl(-/-) mice, which closely resemble the human disease, significantly improves the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, we provide evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial. © 2012 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2012; · 6.04 Impact Factor
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Alessandra Pangrazio,
Barbara Cassani,
Matteo M Guerrini,
Julie C Crockett,
Veronica Marrella,
Luca Zammataro,
Dario Strina,
Ansgar Schulz,
Claire Schlack,
Uwe Kornak, [......],
Anne Durandy,
Despina Moshous,
Ashok Vellodi,
Robert Chiesa,
Paul Veys, Nadia Lo Iacono,
Paolo Vezzoni,
Alain Fischer,
Anna Villa,
Cristina Sobacchi
[show abstract]
[hide abstract]
ABSTRACT: Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2012; 27(2):342-51. · 6.04 Impact Factor
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Alessandra Pangrazio,
Barbara Cassani,
Matteo M Guerrini,
Julie C Crockett,
Veronica Marrella,
Luca Zammataro,
Dario Strina,
Ansgar Schulz,
Claire Schlack,
Uwe Kornak, [......],
Anne Durandy,
Despina Moshous,
Ashok Vellodi,
Robert Chiesa,
Paul Veys, Nadia Lo Iacono,
Paolo Vezzoni,
Alain Fischer,
Anna Villa,
Cristina Sobacchi
[show abstract]
[hide abstract]
ABSTRACT: Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder due to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast-rich, but recently 2 subsets of osteoclast-poor ARO have been recognised as due to defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterisation of 5 additional unpublished patients from 4 unrelated families in which we found 5 novel mutations in the TNFRSF11A gene, including 2 missense and 2 nonsense mutations and a single-nucleotide insertion. Immunological investigation in 3 of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all 5 patients almost completely cured the disease even when carried out in late infancy. Hypercalcaemia was the most important post-transplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. © 2011 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2011; · 6.04 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: In the last decade, the low-density lipoprotein receptor-related protein 5 (LRP5) gene, coding for a coreceptor in the canonical Wnt signalling pathway, has been shown to play an important role in regulating bone mass and to be involved in the pathogenesis of several bone disorders. Here we describe a patient who presented with a clinical picture of Autosomal Dominant Osteopetrosis type I (ADO I), in whom we could identify the first deletion in the LRP5 gene causing increased bone mass. This mutation caused the in-frame deletion of two amino acids in the fourth blade of the first propeller of the protein, namely the highly conserved glycine at position 171 and the following glutamate residue. In vitro studies suggested that the pathogenic effect of this novel mutation could be due to a decreased inhibition of Wnt signalling by the antagonistic proteins sclerostin and Dickkopf-1, encoded respectively by the SOST and DKK1 genes, in the presence of mutated LRP5. Our results highlight an increasing molecular heterogeneity in LRP5-related bone diseases.
Bone 05/2011; 49(3):568-71. · 4.02 Impact Factor
