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Causes 3 Bone 11

Page history last edited by Julie Swihart 14 years, 8 months ago

Van Buchem's Syndrome is the result of a missense mutation. Missense mutations occur during DNA replication when a nucleotide substitution changes the genotype. In Van Buchem's Syndrome, this mutation occurs on the LRP5 gene on chromosome 11[1].


Missense Mutations

          Missense mutations are a type of point mutation, mutations in which one nucleotide base is swapped for another nucleotide base (i.e. pyridimine for pyridimine, purine for purine, purine for pyridimine). These swaps cause DNA code changes, which can then affect the structure and function of the protein that section of DNA is coding for. The result of these mutations may be harmful to the cell or organism if the mutated protein does not perform the same function or does not work at all due to the new amino acid coded for by the mutated nucleotide. However, the mutation may not necessarily have detrimental effects. Conservative mutations occur when there are no functional changes to the amino acid sequence, this is also called a silent mutation. People with conservative mutations may never know they have a mutation, as it does not result in damages[2].




Missense Mutation in LPR5

The missense mutation that occurs in LPR5, causing Van Buchem syndrome, is G171V. In this mutation, Gly171 is being substituted by Val[4]


 *Helpful hint: Read LPR5 page before you attempt to read the following!!!!


           Van Buchem's syndrome is caused by an over-active Wnt receptor channel. The mutation does not actually affect the binding of the FZD-Wnt complex to LPR5. Instead, it does not allow DKK1 to bind to LPR5 and turn off the channel. Why does this happen? It happens because Wnt is a very general activator for stem cell specicfication, In other words it's a 'one size fits most' ligand that tells the cells what to develop into. Since Wnt has so many forms, it can easily adapt to the structural change in the LPR5 protein which results from the missense mutation. The DKK1 on the other hand, is a very specific inhibitor and cannot adapt to the mutation, meaning that it will not bind to the mutated LPR5, so it cannot turn off the channel. When the channel does not get turned off, uncontrolled bone growth will occur.



Van Buchem's Syndrome (home page) 


Page Authors: Emmie Ryan and Julie Swihart



  1. Balemans, Wendy, Jean-Pierre Devolgelaer, Erna Cleiren, Elke Piters, and Emanuelle Caussin. "Novel LRP5 Missense Mutation." Journal of Bone and Mineral Research. 22.5 (2007): 1. Print.
  2. Smith, S.E. "What are missense mutations?." WiseGeek. Web. 27 Oct 2009. .
  3. "Genetics Home Reference." Missense Mutations. 23 10 2009. U.S. National Library of Medicine, Web. 28 Oct 2009. .
  4. Zhang, Yazhou, Yang Wang, Xiaofeng Li, Junhao Mao, and Jie Zheng. "The LRP5 High-Bone-Mass G171V Mutation Disrupts LRP5." Molecular and Celluar Biology. 24.11 (2004): 1. Print.

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