SNX10 and Autosomal Recessive Osteopetrosis

This summary details the association between SNX10 and autosomal recessive osteopetrosis. Multiple independent case reports have identified pathogenic mutations in SNX10, most notably a homozygous stop mutation, c.46C>T (p.Arg16Ter), in affected individuals from consanguineous families (PMID:23123320). The clinical presentations include prominent craniofacial abnormalities such as a prominent forehead and macrocephaly, along with splenomegaly, joint hypermobility, and strabismus, which are consistent with osteopetrosis phenotypes.

Genetic evidence comes from several studies reporting homozygous as well as splice site and frameshift mutations in SNX10 across different cohorts. In one series, nine individuals with an intermediate form of autosomal recessive osteopetrosis were found to harbor segregating SNX10 mutations (PMID:28592808). Other multi‐patient studies have confirmed these findings, with patients also presenting additional features such as hepatomegaly and hydrocephalus (PMID:26970326).

Functional studies strongly support a loss‐of‐function mechanism for SNX10 in the pathogenesis of osteopetrosis. Structural analyses have revealed that truncating mutations, including c.46C>T (p.Arg16Ter), disrupt critical domains involved in vesicular trafficking and osteoclast function. In vitro and animal model experiments have demonstrated impaired osteoclast formation, reduced bone resorption, and abnormal endocytosis (PMID:25212774; PMID:33975343).

Additional multi-patient genetic studies consolidate this association by identifying a broad spectrum of SNX10 mutations in patients with osteopetrosis. These studies not only provide evidence from distinct families, but also include functional confirmation from induced pluripotent stem cell (iPSC) models, further bridging the genetic observations with cellular pathophysiology.

The integration of comprehensive genetic data and robust functional experiments underscores a strong association between pathogenic variants in SNX10 and autosomal recessive osteopetrosis. This broad evidence base, spanning single-case reports to multi-patient studies and mechanistic experiments, supports the clinical validity of SNX10 mutation testing. Its incorporation in diagnostic workflows can guide targeted therapies and support translational research and commercial development initiatives.

Key take‑home: Pathogenic SNX10 mutations, particularly the recurrent c.46C>T (p.Arg16Ter) variant, provide a reliable genetic marker for autosomal recessive osteopetrosis, thereby enhancing early diagnosis and informing management strategies.

References

• European journal of medical genetics • 2013 • Homozygous stop mutation in the SNX10 gene in a consanguineous Iraqi boy with osteopetrosis and corpus callosum hypoplasia PMID:23123320
• Scientific reports • 2017 • SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts PMID:28592808
• Proteins • 2014 • Structure of human SNX10 reveals insights into its role in human autosomal recessive osteopetrosis PMID:25212774
• Journal of cell science • 2021 • An SNX10-dependent mechanism downregulates fusion between mature osteoclasts PMID:33975343
• Pediatric blood & cancer • 2016 • Extending the Spectrum of Radiological Findings in Patients With Severe Osteopetrosis and Different Genetic Backgrounds PMID:26970326

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