Researchers discover that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.

What is it about the extra chromosome inherited in Down syndrome—chromosome 21—that alters brain and body development? Researchers have new evidence that points to a protein called sorting nexin 27, or SNX27. SNX27 production is inhibited by a molecule encoded on chromosome 21. The study shows that SNX27 is reduced in human Down syndrome brains. The extra copy of chromosome 21 means a person with Down syndrome produces less SNX27 protein, which in turn disrupts brain function. What’s more, the researchers showed that restoring SNX27 in Down syndrome mice improves cognitive function and behaviour.

‘In the brain, SNX27 keeps certain receptors on the cell surface—receptors that are necessary for neurons to fire properly,’ said Huaxi Xu, Ph.D., Sanford-Burnham professor and senior author of the study. ‘So, in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects.’
Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly. With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.
Then the team got thinking about Down syndrome. The SNX27-deficient mice shared some characteristics with Down syndrome, so they took a look at human brains with the condition. This confirmed the clinical significance of their laboratory findings—humans with Down syndrome have significantly lower levels of SNX27.

Next, Xu and colleagues wondered how Down syndrome and low SNX27 are connected—could the extra chromosome 21 encode something that affects SNX27 levels? They suspected microRNAs, small pieces of genetic material that don’t code for protein, but instead influence the production of other genes. It turns out that chromosome 21 encodes one particular microRNA called miR-155. In human Down syndrome brains, the increase in miR-155 levels correlates almost perfectly with the decrease in SNX27.

Xu and his team concluded that, due to the extra chromosome 21 copy, the brains of people with Down syndrome produce extra miR-155, which by indirect means decreases SNX27 levels, in turn decreasing surface glutamate receptors. Through this mechanism, learning, memory, and behaviour are impaired.

If people with Down syndrome simply have too much miR-155 or not enough SNX27, could that be fixed? The team explored this possibility. They used a non-infectious virus as a delivery vehicle to introduce new human SNX27 in the brains of Down syndrome mice.

‘Everything goes back to normal after SNX27 treatment. It’s amazing—first we see the glutamate receptors come back, then memory deficit is repaired in our Down syndrome mice,’ said Xin Wang, a graduate student in Xu’s lab and first author of the study. ‘Gene therapy of this sort hasn’t really panned out in humans, however. So we’re now screening small molecules to look for some that might increase SNX27 production or function in the brain.’ Sanford-Burnham Institute

A recent article describes genetic testing of a rare blood cancer called atypical chronic neutrophilic leukaemia (CNL) that revealed a new mutation present in most patients with the disease. The mutation also serves as an Achilles heel, allowing doctors at the University of Colorado Cancer Center to prescribe a never-before-used, targeted treatment. The first patient treated describes his best snowboarding season ever.

‘I’m a crazy sports fan,’ says the patient. ‘I go 30 days a season. I may be the oldest guy snowboarding on the mountain, but I’m not the slowest!’

When he lost a few pounds from what eventually proved to be undiagnosed cancer, the patient was initially pleased. ‘I was lighter and could snowboard better – ride better, jump better,’ he says. Then he took a blood test and his white blood cell count was far in excess of the normal range. His doctor couldn’t find a cause and so they watched and waited. A couple months later, another blood test showed his white count was even higher.

‘That’s when I decided to go to the University of Colorado Hospital,’ he says. There he met Daniel A. Pollyea, MD, MS, CU Cancer Center investigator, assistant professor and clinical director of Leukemia Services at the University of Colorado School of Medicine, and co-author of what would become the recent study.

‘Pollyea said my illness didn’t fit into any major categories,’ the patient says. ‘I could see in his face that he’d run into something abnormal, something new. He was aggressive but didn’t force his own opinion. I saw him reach out to every source he could find – every other specialist he could get in contact with.’

‘He’d been sent from doctor to doctor being told incorrect information,’ Pollyea says. ‘By the time we saw him, his blood counts were going in a bad direction due to the progression of his leukaemia.’

Pollyea had worked on blood cancers since his fellowship training at Stanford University, and through his work there developed a relationship with researchers at the University of Oregon, which had an ongoing project in blood cancers that defied common classifications. Pollyea and his team took a sample from his patient and sent it to Oregon for testing, with the hopes that if they could identify a gene mutation causing this cancer, there might be a chance they could target the mutation with an existing drug.

Sure enough, sequencing showed a mutation in a gene that makes a protein called colony-stimulating factor 3 (CSF3R). Cells with this mutation have uncontrolled growth in the bone marrow, resulting in a leukaemia.

Further studies revealed a drug, ruxolitinib, could effectively target cells with this mutation. Approved to treat another condition, myelofibrosis, just months before, the drug hadn’t previously been considered as a treatment for this type of leukaemia. But with dwindling options, Pollyea and colleagues decided ruxolitinib was worth a try.

‘There were no good alternatives other than to use the ruxolitinib,’ Pollyea says. ‘Our patient became the first person with this condition who received this treatment. His white blood count came down, his other blood counts normalised, and his symptoms virtually disappeared.’

‘I had my best snowboarding season ever,’ says the patient. ‘Good, late season snow here in Colorado. Actually, I’d lived elsewhere and when I first got the disease I wondered if maybe something about moving to Colorado made it happen – you know, the altitude, the lack of oxygen. But now after working with Dr. Pollyea, I realise that I didn’t get sick because I live here, I got cured because I live here. Would I have had this kind of treatment anywhere else? I’m not so sure.’ University of Colorado Cancer Center

A more rapid laboratory test for pregnant women to detect potentially deadly Group B strep (GBS) has been successful at identifying GBS colonisation in six and a half hours, according to the results of a study from The University of Texas Health Science Center at Houston (UTHealth).

The more rapid test could be helpful for the 13 percent of patients who experience pre-term labour before they are screened for GBS, which usually occurs between 35 and 37 weeks of gestation. The current standard test takes 48 hours. Antibiotics can be administered at the time of delivery to kill the bacteria.

‘This new test could change the management of patients who present to labour and delivery with threatened pre-term labour and aren’t expected to deliver right away,’ said Jonathan Faro, M.D., Ph.D., assistant professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at The University of Texas Medical School at Houston, part of UTHealth. ‘It would likely gain use in this patient population, which is a small number, but still very significant clinically. We could target this population and this would help cut down on overuse of resources and minimise our contribution to the increased level of bacterial resistance.’

The new test can also detect antibiotic sensitivities for women who are allergic to penicillin, saving the additional 48 hours the standard test for antibiotic sensitivity takes, Faro said.

GBS is the most common cause of sepsis (blood infection) and meningitis and a frequent cause of pneumonia in newborns, according to the Centers for Disease Control (CDC). The CDC estimates the bacterium, which is passed from mother to child through the birth canal, is carried by 25 to 30 percent of women at any one time. Because GBS has few symptoms, many women do not know they are carriers. In 2001, 1,700 babies less than 1 week old contracted GBS, which can lead to disability and death.

In the study, 356 patients at 35 to 37 weeks of gestation at UT Physicians clinics were tested for GBS using two standard tests and the new test, which provided a high level of validity according to the study results.

Faro is studying an even faster version of the test with the hope it could detect GBS in as little as 30 minutes. That could make a difference for the up to 15 percent of pregnant women who arrive for full-term delivery and have not been screened. Right now, obstetricians must determine whether to give these women intravenous antibiotics automatically or use risk factors, which have been shown to be only half as effective as laboratory tests, to assess whether the patient has the bacteria.

‘Typically, if a patient comes into the emergency room in labour and you don’t know if she carries GBS, you have to treat her with antibiotics,’ Faro said. ‘Everyone is concerned that the overuse of antibiotics is leading to greater resistance to them. Some have expressed concern that by giving penicillin to everyone, we are increasing the number of babies who are getting sick from E. coli sepsis.’ The University of Texas Health Science Center

Researchers at the UCL Institute of Neurology together with international collaborators have identified a new gene, BICD2, which causes both dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraparesis. The team was led by Professor Mary Reilly.
Dominant Congenital Spinal Muscular Atrophy is a disorder of developing anterior horn cells and is characterised by lower limb predominance whereas Hereditary Spastic Paraparesis develops in childhood or adult life and is also a lower limb predominant disorder but of the corticospinal motor neurons.
The importance of this gene for motor nerves is underlined by the simultaneous publication of the same gene causing dominant Congenital Spinal Muscular Atrophy by two other groups.
The identification of the gene by exome sequencing and the subsequent functional work to study the pathogenesis of the disorder formed a major part of the PhD of Dr. Alex Rossor, a PhD student in the MRC Centre for Neuromuscular Diseases in the Institute of Neurology. UCL Institute of Neurology