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An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility.

Riikka E Mäkitie1,2,3, Petra Henning4, Yaming Jiu5,6,7

  • 1Folkhälsan Institute of Genetics Helsinki Finland.

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|July 14, 2021
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Summary

Defective regulation of Rho GTPase activating protein 25 (ARHGAP25) causes severe skeletal fragility due to impaired Rac1 function. This highlights the role of RhoGAP signaling in bone metabolism and familial bone diseases.

Keywords:
BONE MODELING AND REMODELINGCELL/TISSUE SIGNALING ‐ OTHERGENETIC RESEARCHOSTEOGENESIS IMPERFECTAOSTEOPOROSIS

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Area of Science:

  • Genetics and Molecular Biology
  • Skeletal Biology
  • Cellular Signaling

Background:

  • Ras homologous guanosine triphosphatases (RhoGTPases) are crucial for cellular functions like actin remodeling and migration.
  • GTPase-activating proteins (GAPs) downregulate RhoGTPase activity.
  • The role of RhoGTPases in human bone health and disease is not well understood, despite their involvement in bone remodeling.

Purpose of the Study:

  • To investigate the genetic basis of severe, early-onset, autosomal-dominant skeletal fragility in a Finnish family.
  • To identify the molecular mechanisms underlying defective RhoGTPase regulation in skeletal fragility.
  • To explore the role of ARHGAP25 in bone metabolism and its association with fracture risk in the general population.

Main Methods:

  • Exome sequencing to identify genetic variants in affected individuals.
  • Bone histomorphometry to analyze bone structure and turnover.
  • Analysis of ARHGAP25 expression in human monocytes and mouse osteoblasts.
  • Functional studies using osteosarcoma cells overexpressing a mutant ARHGAP25.
  • Structural modeling to assess the impact of the mutation on protein activity.

Main Results:

  • A novel heterozygous missense variant (p.G218R) in ARHGAP25 was identified in a family with severe skeletal fragility.
  • The identified ARHGAP25 mutation decreased GTPase-activating protein (GAP) activity towards Rac1, leading to elevated Rac1 activity.
  • Variants in the ARHGAP25 5' untranslated region (UTR) were associated with bone mineral density (BMD) and fracture risk in population studies.
  • Mutant ARHGAP25 expression resulted in increased cell spreading and membrane ruffling, indicating aberrant Rac1 function.

Conclusions:

  • Defective RhoGTPase regulation due to ARHGAP25 mutation is a cause of severe skeletal fragility.
  • Aberrant Rac1 function resulting from mutated ARHGAP25 leads to abnormal bone metabolism.
  • RhoGAP signaling is critical for bone metabolism, and its dysfunction contributes to familial skeletal fragility and potentially general fracture risk.