In genetics, as in life, surprising things can turn up in unexpected places. That was certainly the case when an international group of researchers found three mutations responsible for a form of hereditary deafness in a gene that is implicated in cancer. The research is published in the July 10 issue of The American Journal of Human Genetics.
This surprising finding happened when researchers from the National Institute on Deafness and Other Communication Disorders (NIDCD), National Cancer Institute (NCI), Baylor College of Medicine, Houston, All India Medical Institute in India, and Punjab and Islamabad Universities in Pakistan were scanning the DNA of over a thousand families with deaf children, searching for genes that could be responsible for inherited forms of deafness. Pooling their data, the researchers narrowed the region of one such gene, which they called DFNB39, to a stretch of DNA on chromosome 7.
Genes are segments of DNA that contain the codes for making proteins, which are the building blocks of all the tissues and organs in the body. Nearly all of the human genetic diseases known by scientists are caused by changes in the protein-coding gene sequences in DNA.
However, there are other parts of genes that do not specify the protein's composition. Instead, these "noncoding" sections regulate the expression of a gene. For example, a regulatory section might turn the gene on or off in one tissue, such as the brain, but not another, such as the heart. Or it might control the timing of the gene's expression, for example by turning it on only during development or leaving it on all the time. Scientists know much less about these noncoding, regulatory sequences than they do about the protein-coding sequences. As a result, fewer human genetic diseases are known to be associated with such sequences.
When the investigators examined the protein-coding sequences of every gene in the DFNB39 region, they came up short. They could find no protein-coding DNA changes in any of the genes. Thus, they concluded the deafness-causing change had to be in a regulatory section. Exploring further, the scientists found three non-coding mutations in the gene that encodes hepatocyte growth factor, or HGF, which is important for the growth and regeneration of liver tissue.
HGF has also been shown to have different and powerful effects in other tissues. Generally, it influences the production and growth of cells, so many scientists study its effects in cancer, fetal development, and wound repair in adults. Until recently, very few mutations had been found in the HGF gene. Those that were found were in the protein-coding parts of the gene and caused cancer-related diseases. There was no reason to expect that mutations in the HGF gene could cause deafness.
So how do mutations in a gene related to cancer cause deafness?
Often, scientists turn to the mouse as a model organism to study the effects of a gene mutation; however, mice with mutations in the coding sequence of the HGF gene die as embryos. Taking another tack, by looking at mice in which the HGF protein was normal, but over-expressed in all tissues, or under-expressed in just a few tissues including the inner ear, the scientists discovered that the mice survived, but were deaf. This led the researchers to wonder if the DFNB39 mutations caused deafness in humans because of over- or under-expression of HGF.
The group also noted that another mechanism of gene regulation, alternate splicing, was at work in the HGF gene, and was producing alternative forms of the protein-called isoforms. The HGF gene produces five isoforms, and potentially a sixth that the team discovered. The NIDCD-led researchers found that one of the three mutations appears to influence the way the HGF gene chooses between some of the isoforms. The other two mutations in the HGF gene occur in a region that may affect the sixth isoform. Subtle differences in these isoforms could be what drive the development of deafness.
The researchers are now working on a "knock-in" mouse model of DFNB39, in which they will make mutations in the mouse gene that are similar to the regulatory mutations they see in deaf humans. They will use the mice to test their ideas about how regulation of this gene plays a role in hereditary deafness.
Contributors to this research include Drs. Julie Schultz and Robert Morell of NIDCD's Laboratory of Molecular Genetics, along with lab chief Dr. Thomas Friedman, NCI's Dr. Glenn Merlino, Dr. Suzanne Leal at Baylor College of Medicine, Dr. Sheikh Riazuddin, of Punjab University, and others.
Taken from http://www.nidcd.nih.gov.