Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Researchers Remove Extra Chromosome From Down's Syndrome ... - Gizmodo

Scientists from the University of Washington have successfully removed an extra copy of chromosome 21 in cell cultures belonging to a person with Down's syndrome. While the breakthrough is unlikely to result in an outright treatment for the condition, it could pave the way for gene therapies in which many of the health conditions associated with the chromosomal disorder can be significantly alleviated.

Down's syndrome is the result of having three copies of chromosome 21 instead of the usual pair. This results in what's called a trisomy — a genetic anomaly that can often result in altered cellular phenotypes and cogenital abnormalities. Extra chromosomes account for almost a quarter of all spontaneous miscarriages, along with conditions like Edwards syndrome and Patau syndrome. But of all trisomies, it's Down's syndrome that accounts for the majority of live births.

As a result of the extra copy of chromosome 21, individuals with Down's syndrome feature characteristic eye, facial, and hand features, as well as a number of medical problems like heart defects, impaired intellect, premature aging and dementia, and certain forms of leukemia.

But now, Li B. Li of the UW Department of Medicine, along with David Russell and Thalia Papayannopoulou, have developed a technique in which they were able to correct trisomy 21 in human cell lines grown in the lab. And they were able to accomplish this by using, what else, pluripotent stem cells.

And indeed, the researchers got the idea while working with stem cells to develop regenerative therapies — what often results in trisomies. To overcome the problem, they used a specialized virus to deliver a foreign gene called TKNEO into a particular spot on chromosome 21. This spot is within a gene called APP, which is located on the long arm of the chromosome. They chose this specific gene because of the way it responds to positive and negative selection under specific conditions.

So, when grown in an environment that selected against TNKEO, the only cells that survived were the ones that spontaneously lost the extra chromosome. This obviously created a desirable selection effect. In addition to this technique, the researchers also employed "point mutations" (single, tiny alterations in DNA base pairs) gene silencing (turning off TKNEO), and the outright deletion of TKNEO.

While the researchers don't see their intervention as a way to treat Down's syndrome outright, they have suggested that resultant gene therapies could treat specific aspects of the condition.

For example, they could create cell therapies for some of the blood-forming disorders associated with the disorder. In addition, Down syndrome patients may eventually be able to have stem cells derived from their own cells, and then have the cells corrected in the lab — after which time they could receive a "stem cell transplant" (minus the extra chromosome), or healthy blood cells derived from their fixed stem cells as a part of their cancer treatments. The team is also hopeful that the discovery could lead to potential cognitive therapies as well.

The study was published in Cell Stem Cell and can be found here.

Top image: Jens Goepfert/Shutterstock.Com.

1 In 500 Men May Carry Extra Chromosome, Raising Risk Of Some Diseases

A comprehensive genetic analysis of over 200,000 men has found that around one in 500 have an extra sex chromosome, with most of them unaware. That's a much higher proportion than previously thought, and it seems to increase their risk of diseases like diabetes and cardiovascular problems.

The new finding comes from data gathered by the UK Biobank project, which is comprehensively tracking the health and genetic data of half a million participants over years. For this study, researchers at Cambridge and Exeter Universities conducted an analysis of genetic data from 200,000 men in the Biobank database, searching for the prevalence of extra sex chromosomes.

Characterized as either X or Y, the sex chromosomes are, as the name suggests, those responsible for the differences between the biological sexes. Usually, females have two X chromosomes, while males normally have an X and a Y. But that's not always the case.

In the new study, the scientists identified 213 men with an extra X, and 143 men with an extra Y, out of the 200,000 men studied. Taking into account the overall health of Biobank participants, the team calculated that about one in 500 men in the general population may carry an extra sex chromosome, which is a much higher percentage than previously thought.

The majority of the men in the study didn't have any indication of the abnormality in their medical records. Of the 213 with the additional X, only 49 (or 23 percent) had been diagnosed with the condition, also known as Klinefelter syndrome. It typically manifests as delayed infertility or puberty, and can be discovered and diagnosed then, but often goes unnoticed. Meanwhile, just one of the 143 men with an extra Y chromosome had been diagnosed, as this condition has even fewer outward signs.

The researchers then investigated the health of these men, and compared them to the rest of the Biobank population. Men with XXY chromosomes had significantly lower levels of testosterone in their blood, and were at a three-fold higher risk of delayed puberty and four times more likely to be childless, suggesting infertility. Men with XYY, on the other hand, seemed to have normal reproductive function.

Men with extra copies of either chromosome were found to be at higher risk of a few other conditions. Their risk of developing type 2 diabetes was three times higher than usual, six times higher for venous thrombosis, three times higher for pulmonary embolism, and four times higher for chronic obstructive pulmonary disease.

The team says it's unsure why the extra chromosome would increase these risks, or why it was similar for both types. But further study could help answer these questions, as well as whether it's useful to start screening people for extra chromosomes as a potential way to prevent the associated diseases.

"Even though a significant number of men carry an extra sex chromosome, very few of them are likely to be aware of this," said Yajie Zhao, first author of the study. "This extra chromosome means that they have substantially higher risks of a number of common metabolic, vascular, and respiratory diseases – diseases that may be preventable."

The research was published in the journal Genetics in Medicine.

Source: Cambridge University

Double Identities Lie Behind Chromosome Disorders - ScienceDaily

Chromosome disorders in sex cells cause infertility, miscarriage and irregular numbers of chromosomes (aneuploidy) in neonates. A new study from Karolinska Institutet published in Nature Genetics shows how chromosome disorders can arise when sex cells are formed.

Sex cells contain a control station for monitoring the mechanism that ensures that the correct numbers of chromosomes are distributed during cell division. Scientists have now shown that there is an alternative distribution mechanism in female sex cells that cause chromosome disorders. Aberrant chromosomes orientate themselves like normal chromosomes, and this ability to adopt double identities protects them from detection by the control centre.

"We believe that this new fundamental mechanism can help to explain why chromosome disorders are so common in female sex cells," says Professor Christer Höög, leader of the study.

The research might eventually lead to new medical treatments able to reduce the risk of foetal damage.

Over 0.3 per cent of children are born with some kind of chromosome disorder. Most develop Downs Syndrome, or obtain the wrong number of sex chromosomes and develop Turner's or Klinefelter's syndrome. Turner's syndrome only occurs in females and is caused when one of the two X chromosomes is missing. Girls with Turner's have arrested development and if no treatment is given do not enter puberty. Klinefelter's syndrome affects males, who receive an extra X chromosome. Symptoms include concentration difficulties, poor motor skills and infertility.

Article: "Bi-orientation of achiasmatic chromosomes in mammalian MI oocytes contributes to aneuploidy"

Anna Kouznetsova, Lisa Lister, Magnus Nordenskjöld, Mary Herbert, Christer Höög

Nature Genetics, 8 July 2007

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