Two Genes Involved in Hereditary Breast and Ovary Cancer Cases

ScienceDaily (Feb. 18, 2011) — Between 5 and 10 percent of breast cancer cases are hereditary, arising because the patient inherits from the father or mother a mutation in a gene that is susceptible to causing the illness. BRCA1 and BRCA2 have already been identified as two of the genes to be monitored. It is estimated that 30 percent of hereditary breast cancer cases are due to mutations in one of these two genes (which suggests, at the same time, that there are other genes involved, but exactly how is still unknown). In any case, few of the mutations found in BRCA1 and BRCA2 could be clearly identified as pathological. The fact is that the mutations found were numerous; their variation even depending on the population.

Biologist Elena Beristain has been investigating the CAPV-EAE population. Concretely, for her study she took 521 patients mainly from the Txagorritxu hospital in the Basque capital city of Vitoria-Gasteiz, and the Cruces hospital in Barakaldo, near Bilbao: 274 patients with breast or ovarian cancer (given that the latter is also associated with mutations in the BRCA1 and BRCA2 genes), 115 family relations of these, and another 132 women who acted as a control population. Ms Beristain molecularly characterised the BCRA1 y BCRA2 genes of these individuals; apart from the exon 10 of the CHEK2 gene, also associated with the illness. Her thesis was defended at the University of the Basque Country (UPV/EHU) and it is entitled, Genetic study amongst women resident in the CAPV-EAE with hereditary breast/ovary cancer.

Could rise to 12 percent

According to the results shown, different types of variations in the genes under study have been found, including pathological ones, neutral ones and those of uncertain significance. As regards the clearly pathological mutations, the frequency is 10 percent. Nevertheless, Ms Beristain stressed that, amongst those sporadic cases of under-40s, that is a especially rare condition: only in one case was a pathological mutation found. This is why she suggested discarding under-35s in this type of research, and in which case the result arrived at in her study rises from 10 percent to 12 percent. In any case, the percentages of pathological mutations found in this genetic study of the CAPV-EAE population turned out to be less than amongst other European populations.

The study has thrown up more data regarding age. For example, the percentages show that, for family-member carriers of mutation in the main genes under study, the accumulated risk of suffering breast cancer at 70 is 69 percent for the BRCA1 and 67 percent for the BRCA2. This means that penetration is not complete and there exists the possibility that this gene does not, in the end, express itself. As regards the data on gender, it is significant that masculine breast cancer is mainly associated with mutations in the BRCA2 gene.

Different mutations in the Autonomous Community of the Basque Country

The variability from population to population in mutations in general is also clear from the results of this thesis. Ms Beristain explained that a great number of alterations, hitherto unrecorded, have been found, and from this she concludes that many of the mutations found in the CAPV-EAE are different from those described for other populations. However, she explains, amongst these, no founder effect mutation was found, i.e. there has been no case of some, many or all Basque patients coming from a small population of individuals having transmitted this common genetic characteristic to all their descendents. However it may be, the new types of mutations found represent a contribution to the already existing variability.

Como Disordered Proteínas Spread de célula a célula, potencial propagação da doença

ScienceDaily (Feb. 18, 2011) — One bad apple is all it takes to spoil the barrel. And one misfolded protein may be all that's necessary to corrupt other proteins, forming large aggregations linked to several incurable neurodegenerative diseases such as Huntington's, Parkinson's and Alzheimer's.

An image of U2OS cells infected with Q91 polygluytamine aggregates (in green) colocalized with intracelluluar expressed (red) Q25.

Stanford biology Professor Ron Kopito has shown that the mutant, misfolded protein responsible for Huntington's disease can move from cell to cell, recruiting normal proteins and forming aggregations in each cell it visits.

Knowing that this protein spends part of its time outside cells "opens up the possibility for therapeutics," he said. Kopito studies how such misfolded proteins get across a cell's membrane and into its cytoplasm, where they can interact with normal proteins. He is also investigating how these proteins move between neuronal cells.

The ability of these proteins to move from one cell to another could explain the way Huntington's disease spreads through the brain after starting in a specific region. Similar mechanisms may be involved in the progress of Parkinson's and Alzheimer's through the brain.

Kopito discussed his research on Feb. 18 at the annual meeting of the American Association for the Advancement of Science in Washington, D.C.

Not all bad

Not all misfolded proteins are bad. The dogma used to be that all our proteins formed neat, well-folded structures, packed together in complexes with a large number of other proteins, Kopito said. But over the past 20 years, researchers have found that as much as 30 percent of our proteins never fold into stable structures. And even ordered proteins appear to have some disordered parts.

Disordered proteins are important for normal cellular functions. Unlike regular proteins, they only interact with one partner at a time. But they are much more dynamic, capable of several quick interactions with many different proteins. This makes them ideal for a lot of the standard communication that happens within a cell for its normal functioning, Kopito said.

But if some of our proteins are always disordered, how do our cells tell which proteins need to be properly folded, and which don't? "It's a big mystery," said Kopito, and one that he's studying. This question has implications for how people develop neurodegenerative diseases, all of which appear to be age-related.

Huntington's disease is caused by a specific mutated protein. But the body makes this mutant protein all your life, so why do you get the disease in later adulthood? Kopito said it's because the body's protective mechanisms stop doing their job as we get older. He said his lab hopes to determine what these mechanisms are.

A bad influence

But it's clear what happens when these mechanisms stop working -- misfolded proteins start recruiting normal versions of the same protein and form large aggregations. The presence of these aggregations in neurons has been closely linked with several neurodegenerative diseases.

Kopito found that the mutant protein associated with Huntington's disease can leave one cell and enter another one, stirring up trouble in each new cell as it progresses down the line. The spread of the misfolded protein may explain how Huntington's progresses through the brain.

This disease, like Parkinson's and Alzheimer's, starts in one area of the brain and spreads to the rest of it. This is also similar to the spread of prions, the self-replicating proteins implicated in mad cow disease and, in humans, Creutzfeldt-Jakob disease. As the misfolded protein reaches more parts of the brain, it could be responsible for the progressive worsening of these diseases.

Now that we know that these misfolded proteins spend part of their time outside of cells, traveling from one cell to another, new drugs could target them there, Kopito said. This could help prevent or at least block the progression of these diseases.

Kopito is currently working to figure out how misfolded proteins get past cell membranes into cells in the first place. It is only once in the cell's cytoplasm that these proteins can recruit others. So these studies could help find ways to keep these mischief-makers away from the normal proteins.

He is also collaborating with biology professor Liqun Luo to track these proteins between cells in the well-mapped fruit fly nervous system. In the future, Kopito said he hopes to link his cell biology work to disease pathology in order to understand the role misfolded proteins play in human disease.

Male Fertility Is in the Bones: First Evidence That Skeleton Plays a Role in Reproduction

ScienceDaily (Feb. 18, 2011) — Researchers at Columbia University Medical Center have discovered that the skeleton acts as a regulator of fertility in male mice through a hormone released by bone, known as osteocalcin.

Researchers have found an altogether unexpected connection between a hormone produced in bone and male fertility. The study shows that the skeletal hormone known as osteocalcin boosts testosterone production to support the survival of the germ cells that go on to become mature sperm.

The research, led by Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University Medical Center, is slated to appear online on February 17 in Cell, ahead of the journal's print edition, scheduled for March 4.

Until now, interactions between bone and the reproductive system have focused only on the influence of gonads on the build-up of bone mass.

"Since communication between two organs in the body is rarely one-way, the fact that the gonads regulate bone really begs the question: Does bone regulate the gonads?" said Dr. Karsenty.

Dr. Karsenty and his team found their first clue to an answer in the reproductive success of their lab mice. Previously, the researchers had observed that males whose skeletons did not secrete a hormone called osteocalcin were poor breeders.

The investigators then did several experiments that show that osteocalcin enhances the production of testosterone, a sex steroid hormone controlling male fertility. As they added osteocalcin to cells that, when in our body produce testosterone, its synthesis increased. Similarly, when they injected osteocalcin into male mice, circulating levels of testosterone also went up.

Conversely, when osteocalcin is not present, testosterone levels drop, which causes a decline in sperm count, the researchers found. When osteocalcin-deficient male mice were bred with normal female mice, the pairs only produced half the number of litters as did pairs with normal males, along with a decrease in the number of pups per litter.

Though the findings have not yet been confirmed in humans, Dr. Karsenty expects to find similar characteristics in humans, based on other similarities between mouse and human hormones.

If osteocalcin also promotes testosterone production in men, low osteocalcin levels may be the reason why some infertile men have unexplained low levels of testosterone.

Skeleton Regulates Male Fertility, But Not Female

Remarkably, although the new findings stemmed from an observation about estrogen and bone mass, the researchers could not find any evidence that the skeleton influences female reproduction.

Estrogen is considered one of the most powerful hormones that control bone; when ovaries stop producing estrogen in women after menopause, bone mass rapidly declines and can lead to osteoporosis.

Sex hormones, namely estrogen in women and testosterone in men, have been known to affect skeletal growth, but until now, studies of the interaction between bone and the reproductive system have focused only on how sex hormones affect the skeleton.

"We do not know why the skeleton regulates male fertility, and not female. However, if you want to propagate the species, it's probably easier to do this by facilitating the reproductive ability of males," said Dr. Karsenty. "This is the only rationale I can think of to explain why osteocalcin regulates reproduction in male and not in female mice."

Other Novel Functions of Osteocalcin Reported Earlier

The unexpected connection between the skeleton and male fertility is one of a string of surprising findings in the past few years regarding the skeleton. In previous papers, Dr. Karsenty has found that osteocalcin helps control insulin secretion, glucose metabolism and body weight.

"What this work shows is that we know so little physiology, that by asking apparently naïve questions, we can make important discoveries," Dr. Karsenty says. "It also shows that bone exerts an important array of functions all affected during the aging process. As such, these findings suggest that bone is not just a victim of the aging process, but that it may be an active determinant of aging as well."

Next Steps and Potential Drug Development

Next, the researchers plan to determine the signaling pathways used by osteocalcin to enhance testosterone production.

And as for potential drug development, since the researchers have also identified a receptor of osteocalcin, more flexibility in designing a drug that mimics the effect of osteocalcin is expected.

Whether it's for glucose metabolism or fertility, says Dr. Karsenty, knowing the receptor will make it easier for chemists to develop a compound that will bind to it.

"This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is a regulator of reproduction," said Dr. Karsenty.