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Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young

Isabel R Orriss1, Stuart Lanham2, Dawn Savery3

  • 1Department of Comparative Biomedical Sciences, Royal Veterinary College, Camden, London, NW1 0TU, UK.

Scientific Reports
|February 22, 2018
PubMed

Insights

Neural tube defect (NTD) mutations, particularly in Wnt/planar cell polarity (PCP) pathway genes, can independently reduce bone mass in mice. This suggests shared genetic networks between spina bifida and bone development.

Area of Science:

  • Developmental Biology
  • Genetics
  • Orthopedics

Background:

  • Fractures are common in children with spina bifida, a neural tube defect (NTD).
  • Wnt/planar cell polarity (PCP) pathway mutations are linked to NTDs, but their direct impact on bone mass is unclear.
  • Understanding shared genetic factors could reveal mechanisms underlying bone fragility in NTDs.

Purpose of the Study:

  • To investigate whether Wnt/PCP pathway disruption, associated with NTDs, independently affects bone mass.
  • To examine the role of specific NTD-associated genes (Vangl2, Celsr1, Pax3, Zic2) in bone structure.
  • To identify shared genetic networks between NTDs and bone properties.

Main Methods:

  • Confirmed Wnt/PCP component expression in osteoblasts and osteoclasts in vitro.
  • Utilized microcomputed tomography (µCT) to compare tibial bone structure in mice with NTD-associated mutations versus wild-type littermates.
  • Performed bioinformatic analysis to document shared genetic networks between NTDs and bone traits.

Main Results:

  • Disruption of Vangl2 or Celsr1 mutations significantly reduced trabecular bone mass and tibial cortical thickness.
  • Pax3 mutations had minimal effects on bone mass.
  • Zic2 mutations altered tibia/fibula junction position and diminished proximal tibial cortical bone.
  • Identified 46 genes involved in neural tube closure with bone-related ontologies.

Conclusions:

  • Wnt/PCP pathway disruption and Zic2 mutations are linked to reduced bone mass, independent of NTDs.
  • Shared genetic networks exist between spina bifida risk and bone structure.
  • Genetic variants predisposing to spina bifida may independently decrease bone mass.

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