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A novel approach for the analysis of de novo point mutations in the human FGFR3 gene

Leicester geneticists and chemists are putting heads together to solve a molecular puzzle underlying genetic disorders.

An ultimate goal in human molecular genetics is to predict the consequences of gene alterations for an individual. Point mutations that involve just a single letter of the DNA code are a major source of genetic variations and a substrate for evolution with the potential to cause diseases.

Recently, Leicester geneticists Esther Signer and Alec Jeffreys have developed a unique technique to study spontaneously arising mutations leading to achondroplasia, the most common form of dwarfism.

Esther Signer said: “The mutation causing this disease lies within the fibroblast growth factor receptor 3 gene and is the most mutable site known in the human genome, especially in older men. We do not know what makes this site so extremely unstable. By catching sperm DNA molecules carrying newly arising achondroplasia mutations and studying the region flanking this mutation, we aim to find out more. Technically, this is extremely challenging and requires a non-standard approach.”

One efficient solution may be offered by using PNA (peptide nucleic acid, see Figure) as a mutation fishing tool. It mimics DNA but lacks all hereditary functions. It can pair with DNA and pick up even single mutations.

Max Ryadnov, a Leicester chemistry lecturer, who collaborates on the project, commented: “PNA acts as a molecular ad-hoc spy in this regard. It is visible to specific DNA sites but the rest of the genetic machinery remains unaware of it. This way PNA extracts and delivers only the data it is assigned to without participating in other processes.”

The project has just received full support from Wellcome Trust enabling the team to realise the goal.

Alec Jeffreys commented: ”We are very excited by this new venture and believe that this work will provide new insight into the mutation dynamics operating inside this gene, and generate an innovative tool to study mutations and other minute DNA alterations elsewhere in the genome.”