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      SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

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          Abstract

          Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand ( RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

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          Most cited references 43

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          Osteopetrosis: genetics, treatment and new insights into osteoclast function.

          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.
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            Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease.

            The mammalian genome encodes 49 proteins that possess a PX (phox-homology) domain, responsible for membrane attachment to organelles of the secretory and endocytic system via binding of phosphoinositide lipids. The PX domain proteins, most of which are classified as SNXs (sorting nexins), constitute an extremely diverse family of molecules that play varied roles in membrane trafficking, cell signalling, membrane remodelling and organelle motility. In the present review, we present an overview of the family, incorporating recent functional and structural insights, and propose an updated classification of the proteins into distinct subfamilies on the basis of these insights. Almost all PX domain proteins bind PtdIns3P and are recruited to early endosomal membranes. Although other specificities and localizations have been reported for a select few family members, the molecular basis for binding to other lipids is still not clear. The PX domain is also emerging as an important protein-protein interaction domain, binding endocytic and exocytic machinery, transmembrane proteins and many other molecules. A comprehensive survey of the molecular interactions governed by PX proteins highlights the functional diversity of the family as trafficking cargo adaptors and membrane-associated scaffolds regulating cell signalling. Finally, we examine the mounting evidence linking PX proteins to different disorders, in particular focusing on their emerging importance in both pathogen invasion and amyloid production in Alzheimer's disease.
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              Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.

              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.
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                Author and article information

                Contributors
                eva-lena.stattin@igp.uu.se
                petra.henning@gu.se
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                7 June 2017
                7 June 2017
                2017
                : 7
                Affiliations
                [1 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Medical Biosciences, Medical and Clinical Genetics, , Umeå University, ; 901 87 Umeå, Sweden
                [2 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, , Uppsala University, ; 751 85 Uppsala, Sweden
                [3 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, , University of Gothenburg, ; 405 30 Gothenburg, Sweden
                [4 ]ISNI 0000 0004 1936 7291, GRID grid.7107.1, Arthritis and Musculoskeletal Medicine Programme, Institute of Medical Sciences, , University of Aberdeen, Foresterhill, ; Aberdeen, AB25 2ZD UK
                [5 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Pediatric Dentistry, Department of Odontology, Faculty of Medicine, , Umeå University, ; 901 87 Umeå, Sweden
                [6 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Pediatrics, , Umeå University, ; 901 87 Umeå, Sweden
                [7 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Mathematics and Mathematical Statistics, Computational Life science Cluster (CLiC), , Umeå University, ; 901 87 Umeå, Sweden
                [8 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Biobank Research, , Umeå University, ; 901 87 Umeå, Sweden
                [9 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Surgical Sciences, Radiology, , Uppsala University, ; 751 85 Uppsala, Sweden
                [10 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Molecular Periodontology, Department of Odontology, Faculty of Medicine, , Umeå University, ; 901 87 Umeå, Sweden
                Article
                2533
                10.1038/s41598-017-02533-2
                5462793
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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