Document Detail

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.
MedLine Citation:
PMID:  23280965     Owner:  NLM     Status:  MEDLINE    
Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than one-half of ARO cases. Since then, 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 3 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 three 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 receptor activator of NF-κB ligand (RANKL), receptor activator of NF-κB (RANK) and osteopetrosis-associated transmembrane protein 1 (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 the 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 the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies.
Alessandra Pangrazio; Anders Fasth; Andrea Sbardellati; Paul J Orchard; Kimberly A Kasow; Jamal Raza; Canan Albayrak; Davut Albayrak; Olivier M Vanakker; Barbara De Moerloose; Ashok Vellodi; Luigi D Notarangelo; Claire Schlack; Gabriele Strauss; Jörn-Sven Kühl; Elena Caldana; Nadia Lo Iacono; Lucia Susani; Uwe Kornak; Ansgar Schulz; Paolo Vezzoni; Anna Villa; Cristina Sobacchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  28     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-18     Completed Date:  2013-10-18     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1041-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
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MeSH Terms
Amino Acid Sequence
Cohort Studies
Genes, Recessive*
Molecular Sequence Data
Osteopetrosis / genetics*
Sequence Homology, Amino Acid
Severity of Illness Index
Sorting Nexins / chemistry,  genetics*
Grant Support
Reg. No./Substance:
0/SNX10 protein, human; 0/Sorting Nexins

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