BioWorld International Correspondent
LONDON - A protein that sucks molecules involved in inflammation down a tube so that its enzymatic site can chop off their last two amino acids could provide a novel target for asthma drugs.
While researchers do not yet know whether the protein, called DPP10, activates or inactivates the molecules it trims, their work so far suggests that it probably plays a key role in the inflammation and narrowing of the airways that leads to difficulty in breathing for asthmatics.
Bill Cookson, professor of human genetics at the University of Oxford, told BioWorld International, "In terms of asthma genetics in general, the discovery of this gene is just another brick in the wall - but it is an unusual brick, because it tells us something new and unexpected about the disease, and it points to a new therapeutic pathway."
Cookson and colleagues at the University of Oxford, along with collaborators at Oxagen plc, of Milton Park, UK, and internationally, have published their findings in Nature Genetics (online publication Oct. 19, 2003). Its title is "Positional cloning of a novel gene influencing asthma from Chromosome 2q14."
The group had carried out a genome-wide screen of 80 families with children who had asthma in 1996. That and subsequent work in 244 families, including 239 children with asthma, allowed them to pinpoint a region of chromosome 2 that was several hundred thousand base pairs long. It appeared the region was inherited by all those with asthma, but not by those without the disease.
As they reported in Nature Genetics, they went on to clone several megabases of that region, and - with the help of scientists at Oxagen - sequenced 500 kilobases. An analysis of single nucleotide polymorphisms in that part of the genome allowed them to detect that the region associated with susceptibility to asthma included a variant of the first exon of the gene encoding DPP10, in the part of the gene that regulates its expression.
The team went on to show that DPP10 was the only gene in the region of the genome. They found that it was expressed in both mice and humans in brain, nervous tissue and the airways. There is more than one way of transcribing the gene: some versions encode a transmembrane domain and therefore are likely to be expressed on the surfaces of cells. Further tests showed that DPP10 also is present on cells of the immune system, such as T cells, and that it is present in the serum.
Analysis showed that the DPP10 variant was significantly more likely to have been inherited by people with severe asthma (p = 0.016), than by those with mild asthma.
The DPP family of proteins have a "beta barrel" - a long, thin tube - at the end of which lies the enzymatic region. Cookson said: "These proteins normally work on simple proteins such as signaling molecules, chemokines or neuropeptides. They are known to cut off two amino acids of the proteins that they interact with, and this normally activates the proteins, but in this case we don't know whether DPP10 activates or inactivates its substrate proteins."
After doing some structural modeling of the active site of DPP10, Cookson and his group worked out what the arrangement of amino acids was likely to be at the N-terminal of its substrate. They searched through the amino acid sequences of all the known chemokines and similar molecules to find out which had the potential to be targets of DPP10.
Cookson said: "The list we came up with was very interesting. It has on it some key chemokines, already known to be associated with asthma and inflammation, such as RANTES, eotaxin and SDF-1a. This work must be confirmed by further experiments, but it suggests that DPP10 could modify key molecules in inflammation, and that would make it a very interesting target for the pharmaceutical industry."
Next, the team aims to find out what DPP10 interacts with, and whether it activates these molecules or inactivates them.
"We also want to know more about its localization in the airways, so we will be comparing its distribution in the airways of people with asthma with that in the airways of those who do not have asthma," Cookson said.