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Cristina Sobacchi - One of the best experts on this subject based on the ideXlab platform.
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autosomal recessive Osteopetrosis type i description of pathogenic variant of tcirg1 gene
Boletín médico del Hospital Infantil de México, 2019Co-Authors: Luis E Chavezguitron, Cristina Sobacchi, Tadeo Cerontorres, Echael Ochoaruiz, Sugey VillegashuescaAbstract:Introduccion: La Osteopetrosis infantil maligna es una condicion rara cuyo origen es la deficiente reabsorcion osea por parte de los osteoclastos. Su diagnostico requiere un alto indice de sospecha. El tratamiento de eleccion es el trasplante alogenico de celulas hematopoyeticas. Los mejores desenlaces ocurren si el procedimiento se lleva a cabo antes de que ocurra dano a los nervios craneales. Caso clinico: Paciente masculino de 8 meses de edad fue referido a la consulta de hematologia por citopenias, hepatomegalia y falla para crecer. Se diagnostico Osteopetrosis infantil maligna basandose en los hallazgos de la exploracion fisica, la alteracion del metabolismo del calcio y el fosforo y la hiperdensidad del hueso. Se obtuvo ADN del paciente y ambos padres; se demostro un heterocigosidad compuesta del gen TCIRG1 con una delecion (c.1809_1818del) no descrita previamente. Conclusiones: Una nueva mutacion patogenica de TCIRG1 se identifico en un paciente mexicano con Osteopetrosis. Se ofrecio trasplante de celulas progenitoras hematopoyeticas como el mejor tratamiento disponible, pero fue rechazado por los padres. Se necesita un reconocimiento temprano y la implementacion del acceso generalizado a este procedimiento
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identificacion de nuevas mutaciones en tcirg1 como causa de Osteopetrosis maligna infantil en dos pacientes mexicanos
Revista alergia Mexico, 2018Co-Authors: Claudia Hernandezmartinez, Cristina Sobacchi, Mara Noemi Guzmanmartinez, Selma Schefflermendoza, Sara Elva Espinosapadilla, Lizbeth BlancasgaliciaAbstract:Background: Osteopetrosis is a heterogeneous group of diseases that are characterized by increased bone density due to abnormalities in osteoclast differentiation or function, which result in a lack of bone resorption. Case reports: Two patients with Osteopetrosis onset since the first months of life, with facial dysmorphia, blindness, deafness, hepatosplenomegaly, hypotonia, neurodevelopmental retardation and bicytopenia. Bone radiographs showed osteosclerosis. They were assessed by different specialists prior to definitive diagnosis. Genetic analysis determined mutations in the TCIRG1 gene. Patient 1 had a homozygous mutation for p.Ile720Alafs*14 identified, which hasn’t been previously reported. Patient 2 had a compound heterozygous mutation: the first one, p.Phe459Leufs*79, and the second one, p.Gly159Argfs*68, none of which has been previously reported as far as we know. Conclusion: The only therapeutic option for patients with Osteopetrosis is hematopoietic stem cell transplantation (HSCT), which should be carried out in the course of the first 3 months of life, before neurological damage occurs. Although Osteopetrosis diagnosis is relatively simple, it is delayed owing to the lack of clinical suspicion.
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genetics of Osteopetrosis
Current Osteoporosis Reports, 2018Co-Authors: Eleonora Palagano, Cristina Sobacchi, Ciro Menale, Anna VillaAbstract:The term Osteopetrosis refers to a group of rare skeletal diseases sharing the hallmark of a generalized increase in bone density owing to a defect in bone resorption. Osteopetrosis is clinically and genetically heterogeneous, and a precise molecular classification is relevant for prognosis and treatment. Here, we review recent data on the pathogenesis of this disorder. Novel mutations in known genes as well as defects in new genes have been recently reported, further expanding the spectrum of molecular defects leading to Osteopetrosis. Exploitation of next-generation sequencing tools is ever spreading, facilitating differential diagnosis. Some complex phenotypes in which Osteopetrosis is accompanied by additional clinical features have received a molecular classification, also involving new genes. Moreover, novel types of mutations have been recognized, which for their nature or genomic location are at high risk being neglected. Yet, the causative mutation is unknown in some patients, indicating that the genetics of Osteopetrosis still deserves intense research efforts.
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Identification of new mutations in TCIRG1 as a cause of infantile malignant Osteopetrosis in two Mexican patients
Colegio Mexicano de Inmunología Clínica y Alergia A.C., 2018Co-Authors: Claudia Hernández-martínez, Cristina Sobacchi, Mara Noemí Guzmán-martínez, Selma Scheffler-mendoza, Sara Elva Espinosa-padilla, Lizbeth Blancas-galiciaAbstract:Background: Osteopetrosis is a heterogeneous group of diseases that are characterized by increased bone density due to abnormalities in osteoclast differentiation or function, which result in a lack of bone resorption. Case reports: Two patients with Osteopetrosis onset since the first months of life, with facial dysmorphia, blindness, deafness, hepatosplenomegaly, hypotonia, neurodevelopmental retardation and bicytopenia. Bone radiographs showed osteosclerosis. They were assessed by different specialists prior to definitive diagnosis. Genetic analysis determined mutations in the TCIRG1 gene. Patient 1 had a homozygous mutation for p.Ile720Alafs*14 identified, which hasn’t been previously reported. Patient 2 had a compound heterozygous mutation: the first one, p.Phe459Leufs*79, and the second one, p.Gly159Argfs*68, none of which has been previously reported as far as we know. Conclusion: The only therapeutic option for patients with Osteopetrosis is hematopoietic stem cell transplantation (HSCT), which should be carried out in the course of the first 3 months of life, before neurological damage occurs. Although Osteopetrosis diagnosis is relatively simple, it is delayed owing to the lack of clinical suspicion
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Osteopetrosis genetics treatment and new insights into osteoclast function
Nature Reviews Endocrinology, 2013Co-Authors: Cristina Sobacchi, Anna Villa, Ansga Schulz, Frase P Coxo, Miep H HelfrichAbstract:Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive Osteopetrosis (ARO), also known as malignant infantile Osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.
Annalisa Frattini - One of the best experts on this subject based on the ideXlab platform.
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molecular and clinical heterogeneity in clcn7 dependent Osteopetrosis report of 20 novel mutations
Human Mutation, 2010Co-Authors: Alessandra Pangrazio, Paul J Orchard, Annalisa Frattini, Michael Pusch, Elena Caldana, Edoardo Lanino, Parag M Tamhankar, Shubha R Phadke, Antonio Gonzalezmeneses Lopez, Ercan MihciAbstract:The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate Osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.
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osteoclast poor human Osteopetrosis due to mutations in the gene encoding rankl
Nature Genetics, 2007Co-Authors: Cristina Sobacchi, Alessandra Pangrazio, Lucia Susani, Annalisa Frattini, Mario Abinun, Matteo M Guerrini, Robbert G M Bredius, Grazia M S Mancini, Andrew J Cant, Nick BishopAbstract:Autosomal recessive Osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive Osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.
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involvement of plekhm1 in osteoclastic vesicular transport and Osteopetrosis in incisors absent rats and humans
Journal of Clinical Investigation, 2007Co-Authors: Liesbeth Van Wesenbeeck, Annalisa Frattini, Paul R. Odgren, Els Van Hul, Fraser P Coxon, Pierre Moens, Bram Perdu, Carole A Mackay, Jeanpierre Timmermans, Filip VanhoenackerAbstract:This study illustrates that Plekhm1 is an essential protein for bone resorption, as loss-of-function mutations were found to underlie the osteopetrotic phenotype of the incisors absent rat as well as an intermediate type of human Osteopetrosis. Electron and confocal microscopic analysis demonstrated that monocytes from a patient homozygous for the mutation differentiated into osteoclasts normally, but when cultured on dentine discs, the osteoclasts failed to form ruffled borders and showed little evidence of bone resorption. The presence of both RUN and pleckstrin homology domains suggests that Plekhm1 may be linked to small GTPase signaling. We found that Plekhm1 colocalized with Rab7 to late endosomal/lysosomal vesicles in HEK293 and osteoclast-like cells, an effect that was dependent on the prenylation of Rab7. In conclusion, we believe PLEKHM1 to be a novel gene implicated in the development of Osteopetrosis, with a putative critical function in vesicular transport in the osteoclast.
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chloride channel clcn7 mutations are responsible for severe recessive dominant and intermediate Osteopetrosis
Journal of Bone and Mineral Research, 2003Co-Authors: Annalisa Frattini, Cristina Sobacchi, Alessandra Pangrazio, Lucia Susani, Mario Abinun, Massimiliano Mirolo, M Andolina, Adrienne M Flanagan, Edwin M Horwitz, Ercan MihciAbstract:Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family. Introduction: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown. Materials and Methods: In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe Osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters. Results and Conclusions: In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe Osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may be associated with CNS involvement and have a very poor prognosis, whereas heterozygous ClCN7 mutations cause a wide range of phenotypes even in the same family, ranging from early severe to nearly asymptomatic forms. These findings have prognostic implications, might complicate prenatal diagnosis of human osteopetroses, and could be relevant to the management of these patients.
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defects in tcirg1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
Nature Genetics, 2000Co-Authors: Annalisa Frattini, Paul J Orchard, Cristina Sobacchi, Silvia Giliani, Mario Abinun, Jan P Mattsson, David Keeling, Ann Katrin Andersson, Pia Wallbrandt, Luigi ZeccaAbstract:Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
Paul J Orchard - One of the best experts on this subject based on the ideXlab platform.
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diagnosis and management of Osteopetrosis consensus guidelines from the Osteopetrosis working group
The Journal of Clinical Endocrinology and Metabolism, 2017Co-Authors: Michael J Econs, Weston P. Miller, Paul J Orchard, Linda A Dimeglio, Karl L Insogna, Michael A Levine, Anna Petryk, Eric T Rush, Dolores M ShobackAbstract:Background Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients. Methods A modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system. Results Consensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile Osteopetrosis has no effective treatment. Conclusions Scarcity of published studies on Osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care.
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Haploidentical transplantation with post-transplant cyclophosphamide following reduced-intensity conditioning for Osteopetrosis: outcomes in three children.
Bone Marrow Transplantation, 2016Co-Authors: T. L. Bahr, Nicole Sando, Paul J Orchard, Troy C. Lund, Weston P. MillerAbstract:Haploidentical transplantation with post-transplant cyclophosphamide following reduced-intensity conditioning for Osteopetrosis: outcomes in three children
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molecular and clinical heterogeneity in clcn7 dependent Osteopetrosis report of 20 novel mutations
Human Mutation, 2010Co-Authors: Alessandra Pangrazio, Paul J Orchard, Annalisa Frattini, Michael Pusch, Elena Caldana, Edoardo Lanino, Parag M Tamhankar, Shubha R Phadke, Antonio Gonzalezmeneses Lopez, Ercan MihciAbstract:The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate Osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.
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human osteoclast poor Osteopetrosis with hypogammaglobulinemia due to tnfrsf11a rank mutations
American Journal of Human Genetics, 2008Co-Authors: Matteo M Guerrini, Cristina Sobacchi, Alessandra Pangrazio, Arbara Cassani, Mario Abinu, Sara Sebnem Kilic, Daniele Moratto, Evelina Mazzolari, Jill Claytonsmith, Paul J OrchardAbstract:Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause Osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known Osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.
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defects in tcirg1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
Nature Genetics, 2000Co-Authors: Annalisa Frattini, Paul J Orchard, Cristina Sobacchi, Silvia Giliani, Mario Abinun, Jan P Mattsson, David Keeling, Ann Katrin Andersson, Pia Wallbrandt, Luigi ZeccaAbstract:Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
Luigi Zecca - One of the best experts on this subject based on the ideXlab platform.
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defects in tcirg1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
Nature Genetics, 2000Co-Authors: Annalisa Frattini, Paul J Orchard, Cristina Sobacchi, Silvia Giliani, Mario Abinun, Jan P Mattsson, David Keeling, Ann Katrin Andersson, Pia Wallbrandt, Luigi ZeccaAbstract:Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
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Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis.
Nature genetics, 2000Co-Authors: Annalisa Frattini, Paul J Orchard, Cristina Sobacchi, Silvia Giliani, Mario Abinun, Jan P Mattsson, David Keeling, Ann Katrin Andersson, Pia Wallbrandt, Luigi ZeccaAbstract: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 Osteopetrosis1, 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 differentiation2,3. 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 osteoclasts2,4,5,6. 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.
Mario Abinun - One of the best experts on this subject based on the ideXlab platform.
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osteoclast poor human Osteopetrosis due to mutations in the gene encoding rankl
Nature Genetics, 2007Co-Authors: Cristina Sobacchi, Alessandra Pangrazio, Lucia Susani, Annalisa Frattini, Mario Abinun, Matteo M Guerrini, Robbert G M Bredius, Grazia M S Mancini, Andrew J Cant, Nick BishopAbstract:Autosomal recessive Osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive Osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.
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chloride channel clcn7 mutations are responsible for severe recessive dominant and intermediate Osteopetrosis
Journal of Bone and Mineral Research, 2003Co-Authors: Annalisa Frattini, Cristina Sobacchi, Alessandra Pangrazio, Lucia Susani, Mario Abinun, Massimiliano Mirolo, M Andolina, Adrienne M Flanagan, Edwin M Horwitz, Ercan MihciAbstract:Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family. Introduction: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown. Materials and Methods: In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe Osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters. Results and Conclusions: In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe Osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may be associated with CNS involvement and have a very poor prognosis, whereas heterozygous ClCN7 mutations cause a wide range of phenotypes even in the same family, ranging from early severe to nearly asymptomatic forms. These findings have prognostic implications, might complicate prenatal diagnosis of human osteopetroses, and could be relevant to the management of these patients.
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defects in tcirg1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
Nature Genetics, 2000Co-Authors: Annalisa Frattini, Paul J Orchard, Cristina Sobacchi, Silvia Giliani, Mario Abinun, Jan P Mattsson, David Keeling, Ann Katrin Andersson, Pia Wallbrandt, Luigi ZeccaAbstract:Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis
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Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive Osteopetrosis.
Nature genetics, 2000Co-Authors: Annalisa Frattini, Paul J Orchard, Cristina Sobacchi, Silvia Giliani, Mario Abinun, Jan P Mattsson, David Keeling, Ann Katrin Andersson, Pia Wallbrandt, Luigi ZeccaAbstract: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 Osteopetrosis1, 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 differentiation2,3. 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 osteoclasts2,4,5,6. 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.
