SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

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.

Snx10 and PIKfyve are required for lysosome formation in osteoclasts

“…Our cofractionation and localization experiments indicate interactions between PIKfyve and Snx10, the sorting nexin that causes osteopetrorickets when mutated in mice or humans . PIKfyve and Snx10 cofractionated with early endosomes and they coprecipitated from cell lysates, suggesting their direct interaction or participation in a multiprotien complex.…”

“…Our cofractionation and localization experiments indicate interactions between PIKfyve and Snx10, the sorting nexin that causes osteopetrorickets when mutated in mice or humans. 10,26,27 PIKfyve and Snx10 cofractionated with early endosomes and they coprecipitated from cell lysates, suggesting their direct interaction or participation in a multiprotien complex. Consistent with this, colocalization of Snx10 and PIKfyve was observed by immunofluorescence of osteoclasts and gastric zymogenic cells, another cell type whose function was shown by us to be severely compromised by Snx10 mutations.…”

Intermediate autosomal recessive osteopetrosis with a large noncoding deletion in SNX10: A case report

“…(osteopetrosis-associated transmembrane protein 1), and SNX10 (sorting nexin 10) account for 1-5% of ARO cases each. [3][4][5][6][7][8] ARO occurs in an estimated 1 in 250 000 people. In addition, a form termed exceptional intermediate autosomal recessive osteopetrosis (IARO) has been described, with mutations in CLCN7, PLEKHM1 (pleckstrin homology domain-containing family M with RUN domain-member 1), and TCIRG1.…”

“…Many genes are implied in ARO such as TCIRG1 (T‐cell immune regulator 1) and CLCN7 (chloride voltage‐gated channel 7), which are responsible for 70% of genetically confirmed ARO. Four additional genes RANKL (receptor activator of NF‐κB ligand), RANK (receptor activator of NF‐κB), OSTM1 (osteopetrosis‐associated transmembrane protein 1), and SNX10 (sorting nexin 10) account for 1‐5% of ARO cases each . ARO occurs in an estimated 1 in 250 000 people.…”

R51Q SNX10 induces osteopetrosis by promoting uncontrolled fusion of monocytes to form giant, non-functional osteoclasts

“…Subsequent studies have revealed additional mutations in SNX10, including nonsense, mis-sense, and splicing defect mutations, that cause ARO in patients of diverse ethnic origins in Europe, North America and Asia. It is currently estimated that mutations in SNX10 account for 5% of ARO cases globally (Palagano et al, 2018;Pangrazio et al, 2013;Stattin et al, 2017). The specific symptoms of patients carrying distinct SNX10 mutations vary, but several symptoms are characteristic; these include early age of onset, significantly increased bone mass, anemia, hepatosplenomegaly, and impaired vision and hearing that are caused by gradual closure of skull foramina arising from reduced bone resorption.…”