Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Relaxin is a reproductive hormone that means what its name suggests. It relaxes salient parts of an expectant mother’s body during pregnancy and parturition labor. Relaxin also plays a hand in forming new blood vessels and in inflammation. But understanding just how it accomplishes this busywork has been hampered by the invisibility of relaxin’s receptors.
Now scientists at Stanford University have coaxed these two bashful receptors out of the closet. Their report in Science, dated Jan. 25, 2002, bears the title: “Activation of orphan receptors by the hormone relaxin.” Its senior author is reproductive biologist Aaron Hsueh.
“Identification of relaxin receptors,” he told BioWorld Today, “allows future design of drugs for the treatment of premature and prolonged labor. Identifying these receptors in heart, brain, kidney and other nonreproductive tissues,” Hsueh added, “highlights the important role of this hormone in congestive heart failure, brain function, kidney infarct and skin remodeling.
“Relaxin was discovered in 1926,” Hsueh continued, “and its two G protein-coupled transmembrane receptors were identified three-quarters of a century later [as he reported in the Science paper] due to the progress of the Human Genome Project. The two relaxin receptors,” he went on, “were found based on GenBank searches of human genes with similarity to a receptor originally found in the snail highlighting the importance of evolutionary conservation.”
On that score, an accompanying editorial titled, “This hormone has been relaxin’ too long!” remarks on “the structural similarity of [the two relaxin hormones] to receptors for other reproductive peptide hormones, such as luteinizing hormone and follicle-stimulating hormone, suggesting that all three of these hormone receptors may share a common evolutionary origin.”
Hseuh’s paper notes, “The wide and divergent distribution of the two relaxin receptors implicates their roles in reproductive, brain, renal, cardiovascular and other functions.”
The relaxin hormone is secreted by a bright yellow ovarian body, the corpus luteum, right after ovulation the starting gun of pregnancy. It eases the birth process by causing the hip bones and cervix to soften and expand the birth canal. Relaxin also keeps the uterus from contracting prematurely and may contribute to the timing of labor pains.
However, the editorial drapes a damp blanket over these putative applications: “In clinical trials with recombinant human relaxin,” it observed, “the peptide hormone failed to show any effect on cervical contraction. These results have proved something of a death-knell for researchers interested in exploiting relaxin for treating disorders of labor onset.”
But the same editorial concluded: “Discovery of the receptors for relaxin should stimulate renewed interest in the action and pharmacology of these hormones. The new findings will accelerate the development of drugs that act as antagonists or agonists of relaxin, leading to better treatments for wound healing, fibrosis and alleviation of postmenopausal symptoms.”
Hereditary Hemochromatosis Proves Non-Starter; Even Homozygous Mutation Carriers Are Rarely Ill
Until recently, hereditary hemochromatosis (HH) was thought to be the commonest genetic disorder of Europeans. Now, one of the largest DNA-based genetic epidemiological studies ever conducted finds it to be relatively rare and mild.
HH is a disorder of iron metabolism marked by excessive absorption of ingested iron and its deposition in tissue especially liver, pancreas and skin. It can cause cirrhosis of the liver and “bronze” diabetes. Eventually, heart failure may occur, the result of overdosing orally on iron, or receiving too many blood transfusions.
Scientists at Scripps Research Institute in La Jolla, Calif., report their findings in The Lancet, dated Jan. 19, 2002, under the title: “Penetrance of 845G >(C282Y) HFE hereditary hemochromatosis mutation in the U.S.A.”
It examined the DNA and clinical data of some 41,000 patients, looking for the HH genetic disease. Although the mutant gene is common, even people carrying two copies of the defective allele are very unlikely to become ill from this homozygous trait, or have their life spans shortened. In consequence, the authors speculate that other factors in addition to the gene mutation account for the actual disease.
Only five of every 1,000 Europeans and Americans of European descent are HH homozygous, having inherited the defect from both parents. The authors point out that the few patients with severe symptoms should be promptly diagnosed so they can be treated, simply and effectively, by removing iron from their bodies via frequently drawing blood as in blood donations.
Antibodies Against Huntington’s Disease Mutant Proteins Seen As Potential Therapeutic Agents
Huntington’s disease (HD) is an invariably fatal neurodegenerative disorder that afflicts a quarter-million victims in the U.S., and some 6,000 in the UK. HD is caused by abnormal expansion of CAG (cytosine-adenine-guanine) nucleotide repeats in DNA. These constantly expanding iterations translate into an extended polyglutamine (polyQ) stretch in exon 1 of the huntingtin protein (htt). Mutant htt with more than 40 CAG repeats induces death in neurons of the brain’s striatum and cortex.
What activates that cell-death pathway? One answer is proposed by a paper in the February issue of Nature Cell Biology. It’s title: “Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity.” The paper’s co-authors are at the California Institute of Technology in Pasadena.
They generated monoclonal antibodies that bind the epitopes of PolyQ and other relevant proteins in exon 1, with a view to perturbing the neuronal cell-death pathway in vitro. “The most important experiments regarding side effects of this potential therapeutic agent,” their paper concludes, “will need to be done in animal models.”