BioWorld International Correspondent
LONDON - A faulty gene responsible for causing inherited blindness in chickens could hold the key to understanding many common diseases that afflict humans, including hypertension, heart disease, diabetes, obesity, stroke and low-birth weight.
The gene defect affects a protein in chickens that normally plays a role in converting light into a nerve impulse in the cone cells of the retina.
Researchers who carried out the study said that a similar mutation in humans could be responsible for an inherited eye disorder called cone-rod dystrophy.
Doug Lester, lecturer in medical biotechnology at the University of Abertay Dundee in Scotland, told BioWorld International: "The gene that we have identified in chickens may also play a role in predisposing people to hypertension, obesity, diabetes and low-birth weight. These diseases are big killers in the Western world, and if we can understand the genetics and physiology behind them, we have a much better chance of developing appropriate therapies."
Lester and his team, with collaborators at Leeds University and the Roslin Institute in Edinburgh, Scotland, set out to determine the genetic mutation responsible for a type of inherited blindness in chickens, called retinopathy globe enlarged (RGE). That causes the affected birds to go blind within six to eight weeks of hatching.
Results from their study have been published in the November 2006 issue of the investigative journal Ophthalmology & Visual Science. The title of the paper is "Mutation in the Guanine Nucleotide-Binding Protein beta-3 Causes Retinal Degeneration and Embryonic Mortality in Chickens."
The team used linkage analysis to map the gene responsible for the condition to an area on chromosome 1. They sequenced candidate genes that lay in that area and discovered that one of them - encoding the guanine nucleotide-binding protein beta-3 (GNB3) - had a deletion of three base pairs. That mutation had the effect of deleting a highly conserved amino acid residue in one of the domains of GNB3, with the result that the spatial configuration of the folded protein changed.
Guanine nucleotide-binding proteins, also known as G-proteins or transducins, play an important role in transducing signals such as those mediated by hormones or neurotransmitters, or by sensory stimuli, such as light, into nerve impulses.
Interestingly, previous studies by others already had implicated a mutant form of GNB3 in many different human diseases. This mild mutant, which results in 40 percent of GNB3 protein produced being spliced abnormally, is present at a high rate in many human populations. It is found in 90 percent of Africans, 80 percent of Aborigines and 30 percent of Europeans.
Lester said: "It has been suggested that it is a 'thrifty' mutation, which helps people survive starvation periods, but which - now that people are eating a Western diet - predisposes them to diseases such as diabetes, heart disease and obesity."
GNB3 is particularly highly expressed in the cone cells of the retina, but also is present throughout the body. That protein, like all G-proteins, binds to a family of proteins called seven-transmembrane proteins throughout the body, not just in the eye, in order to transmit signals into cells.
The team noticed that the chickens with the newly identified mutant gene also had a high mortality rate of embryos. That suggested to the researchers that the birds also might be predisposed to the same group of diseases. Lester said, "If they are, then they would provide good animal models for testing new therapies for hypertension, for example."
Further studies now are under way to see if the chickens also suffer from hypertension, and if humans with inherited retinal degeneration also have mutations in the same gene.
Lester concluded: "We need to find out next whether the mutation is a type that causes loss of function of the manufactured protein, or one that gives the altered protein a new function. Either way, we have ideas about how we might be able to correct what goes wrong, using gene therapy."
Next on the agenda will be the manufacture of transgenic mice that have the human form of mutant GNB3, and those that have the chicken form of mutant GNB3. By comparing the physiology of these two forms of mice, the researchers suggested, they will be able to elucidate more information about the mutation, and how it affects the animals' metabolism.