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SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Journal article
Authors E. L. Stattin
Petra Henning
J. Klar
E. McDermott
C. Stecksen-Blicks
P. E. Sandstrom
T. G. Kellgren
P. Ryden
G. Hallmans
T. Lonnerholm
A. Ameur
M. H. Helfrich
F. P. Coxon
N. Dahl
J. Wikstrom
Ulf H Lerner
Published in Scientific Reports
Volume 7
Issue 1
Pages 3012
ISSN 2045-2322
Publication year 2017
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 3012
Language en
Keywords autosomal-recessive osteopetrosis, renal tubular-acidosis, malignant, osteopetrosis, dc-stamp, insights, disease, bone, calcification, association, families, Science & Technology - Other Topics
Subject categories Medical Genetics


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 Vasterbotten 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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