SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Eva-Lena Stattin; Petra Henning; Joakim Klar; Emma McDermott; Christina Stecksen-Blicks; Per-Erik Sandström; Therese G. Kellgren; Patrik Rydén; Göran Hallmans; Torsten Lönnerholm; Adam Ameur; Miep H. Helfrich; Fraser P. Coxon; Niklas Dahl; Johan Wikström; Ulf H. Lerner

doi:10.1038/s41598-017-02533-2

SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Eva-Lena Stattin, Petra Henning, Joakim Klar, Emma McDermott, Christina Stecksen-Blicks, Per-Erik Sandström, Therese G. Kellgren, Patrik Rydén, Göran Hallmans, Torsten Lönnerholm, Adam Ameur, Miep H. Helfrich, Fraser P. Coxon, Niklas Dahl, Johan Wikström, Ulf H. Lerner

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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.

Original language	English
Article number	3012
Pages (from-to)	1-16
Number of pages	16
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-02533-2
Publication status	Published - 7 Jun 2017

Bibliographical note

Acknowledgements
We sincerely thank the patients and family members who participated in this study. We would also like to thank Stefan Esher, Umeå University, for help with genealogy, and Anna Westerlund for excellent technical assistance. This work was supported by grants from the FOU, at the Umeå university hospital, and the Medical Faculty at Umeå University. The work at University of Gothenburg was supported by grants from The Swedish Research Council, the Swedish Rheumatism Association, the Royal 80-Year Fund of King Gustav V, ALF/LUA research grant from Sahlgrenska University Hospital in Gothenburg and the Lundberg Foundation. The work at the University of Gothenburg and the University of Aberdeen was supported by Euroclast, a Marie Curie FP7-People-2013-ITN: # 607446.

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SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts
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Stattin, E.-L., Henning, P., Klar, J., McDermott, E., Stecksen-Blicks, C., Sandström, P.-E., Kellgren, T. G., Rydén, P., Hallmans, G., Lönnerholm, T., Ameur, A., Helfrich, M. H., Coxon, F. P., Dahl, N., Wikström, J., & Lerner, U. H. (2017). SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts. Scientific Reports, 7, 1-16. Article 3012. https://doi.org/10.1038/s41598-017-02533-2

Stattin, E-L, Henning, P, Klar, J, McDermott, E, Stecksen-Blicks, C, Sandström, P-E, Kellgren, TG, Rydén, P, Hallmans, G, Lönnerholm, T, Ameur, A, Helfrich, MH, Coxon, FP, Dahl, N, Wikström, J & Lerner, UH 2017, 'SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts', Scientific Reports, vol. 7, 3012, pp. 1-16. https://doi.org/10.1038/s41598-017-02533-2

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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 V{\"a}sterbotten 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.",

author = "Eva-Lena Stattin and Petra Henning and Joakim Klar and Emma McDermott and Christina Stecksen-Blicks and Per-Erik Sandstr{\"o}m and Kellgren, {Therese G.} and Patrik Ryd{\'e}n and G{\"o}ran Hallmans and Torsten L{\"o}nnerholm and Adam Ameur and Helfrich, {Miep H.} and Coxon, {Fraser P.} and Niklas Dahl and Johan Wikstr{\"o}m and Lerner, {Ulf H.}",

note = "Acknowledgements We sincerely thank the patients and family members who participated in this study. We would also like to thank Stefan Esher, Ume{\aa} University, for help with genealogy, and Anna Westerlund for excellent technical assistance. This work was supported by grants from the FOU, at the Ume{\aa} university hospital, and the Medical Faculty at Ume{\aa} University. The work at University of Gothenburg was supported by grants from The Swedish Research Council, the Swedish Rheumatism Association, the Royal 80-Year Fund of King Gustav V, ALF/LUA research grant from Sahlgrenska University Hospital in Gothenburg and the Lundberg Foundation. The work at the University of Gothenburg and the University of Aberdeen was supported by Euroclast, a Marie Curie FP7-People-2013-ITN: # 607446.",

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AU - Stattin, Eva-Lena

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AU - Klar, Joakim

AU - McDermott, Emma

AU - Stecksen-Blicks, Christina

AU - Sandström, Per-Erik

AU - Kellgren, Therese G.

AU - Rydén, Patrik

AU - Hallmans, Göran

AU - Lönnerholm, Torsten

AU - Ameur, Adam

AU - Helfrich, Miep H.

AU - Coxon, Fraser P.

AU - Dahl, Niklas

AU - Wikström, Johan

AU - Lerner, Ulf H.

N1 - Acknowledgements We sincerely thank the patients and family members who participated in this study. We would also like to thank Stefan Esher, Umeå University, for help with genealogy, and Anna Westerlund for excellent technical assistance. This work was supported by grants from the FOU, at the Umeå university hospital, and the Medical Faculty at Umeå University. The work at University of Gothenburg was supported by grants from The Swedish Research Council, the Swedish Rheumatism Association, the Royal 80-Year Fund of King Gustav V, ALF/LUA research grant from Sahlgrenska University Hospital in Gothenburg and the Lundberg Foundation. The work at the University of Gothenburg and the University of Aberdeen was supported by Euroclast, a Marie Curie FP7-People-2013-ITN: # 607446.

PY - 2017/6/7

Y1 - 2017/6/7

N2 - 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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JF - Scientific Reports

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SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Abstract

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