Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS

Eur J Hum Genet. 2010 Jun;18(6):733-6. doi: 10.1038/ejhg.2009.225. Epub 2010 Jan 13.


A cis-regulatory sequence also known as zone of polarizing activity (ZPA) regulatory sequence (ZRS) located in intron 5 of LMBR1 is essential for expression of sonic hedgehog (SHH) in the developing posterior limb bud mesenchyme. Even though many point mutations causing preaxial duplication defects have been reported in ZRS, the underlying regulatory mechanism is still unknown. In this study, we analyzed the effect on transcription factor binding of a novel ZRS point mutation (463T>G) in a Pakistani family with preaxial polydactyly and triphalangeal thumb. Electrophoretical mobility shift assay demonstrated a marked difference between wild-type and the mutant probe, which uniquely bound one or several transcription factors extracted from Caco-2 cells. This finding supports a model in which ectopic anterior SHH expression in the developing limb results from abnormal binding of one or more transcription factors to the mutant sequence.

Publication types

  • Case Reports

MeSH terms

  • Base Sequence
  • Caco-2 Cells
  • Family
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Pedigree
  • Point Mutation / physiology
  • Polydactyly / complications
  • Polydactyly / genetics*
  • Polydactyly / metabolism
  • Protein Binding
  • Regulatory Elements, Transcriptional / genetics*
  • Substrate Specificity
  • Thumb / abnormalities*
  • Transcription Factors / metabolism*


  • LMBR1 protein, human
  • Membrane Proteins
  • Transcription Factors