Scientists have identified the genetic cause of a rare skin condition that causes the hands and feet to turn white and spongy when exposed to water.
The study, led by researchers from Queen Mary, University of London, has provided scientists with an insight into how the skin barrier functions and could help with research into a variety of conditions.
Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) is a rare condition in which individuals have thickened, yellowish skin over their palms and soles, thickened nails and suffer from excessive sweating. When their hands and feet are exposed to water, the skin quickly turns white and spongy and individuals are prone to fungal infections.
While prevalence in the general population is estimated at one in 40,000 it is much higher in northern Sweden (up to one in 200 people), where a single ancestral genetic mutation is believed to have originated and then subsequently passed down from generation to generation.
A team led by David Kelsell, Professor of Human Molecular Genetics at Queen Mary studied DNA from a number of families of British and Swedish origin in which the skin condition is present. Using high throughput DNA sequencing methods they were able to pin down the underlying cause of the condition to mutations in the AQP5 gene, which encodes a water channel protein known as aquaporin 5. All individuals who have inherited an AQP5 mutation will present with this rare skin condition.
Professor Kelsell, from the Blizard Institute at Barts and The London School of Medicine and Dentistry, Queen Mary, said: ‘Aquaporins are a family of proteins known as ‘the plumbing system for cells’ as they form pores which allow water to flow through cells rapidly.
‘We knew aquaporin 5 was present in high amounts in the sweat glands, salivary glands and tear ducts – routes by which the body loses water. Here we’ve demonstrated it is also found in the skin, with higher amounts in the hands and feet.’
Co-author Dr Diana Blaydon, also from the Blizard Institute, explained: ‘The AQP5 gene mutation appears to result in a protein that has a wider channel than usual, forming a bigger pore in the cell membrane allowing more water to permeate it.’
Further work is needed to understand exactly how the mutations identified and the associated changes in the skin barrier lead to NEPPK .
Professor Kelsell added: ‘While we’ve studied aquaporins in the skin, these results also give us an idea of what might be happening in internal aquaporins, which are found in structures throughout the body, including the kidneys, cornea and lungs.’ Queen Mary, University of London

A large-scale, international study on the genes involved in epilepsy has uncovered 25 new mutations on nine key genes behind a devastating form of the disorder during childhood.
Among those were two genes never before associated with this form of epilepsy, one of which previously had been linked to autism and a rare neurological disorder, for which an effective therapy already has been developed.
The findings suggest a new direction for developing genome-wide diagnostic screens for new-borns to identify who is at risk for epilepsy and potentially to develop precise therapies for the condition.
The results are the first to emerge from a set of epilepsy-genetics projects known as EPGP and Epi4K, which were launched by the National Institutes of Health in 2007 and 2012, respectively, and involve more than 40 institutions on three continents. While UC San Francisco and Duke University serve as the administrative hubs, the projects involve a team of nearly 150 scientists across 25 specialities, in the hopes of generating this type of advance on the intractable disease.
‘The limitations of what we currently can do for epilepsy patients are completely overwhelming,’ said Daniel Lowenstein, MD, a UCSF neuroscientist and renowned epilepsy expert who, along with Ruben Kuzniecky, MD, from New York University, is overseeing the Epilepsy Phenome/Genome Project (EPGP). ‘More than a third of our patients are not treatable with any medication, so the idea of finding specific drug targets, instead of a drug that just bathes the brain and may cause problems with normal brain function, is very appealing.’
The global team started with the most severe forms of the disorder, known as epileptic encephalopathies (EE), which affect roughly one in 2,000 children, often before their first birthdays. Many of these children also experience other severe disabilities, including autism or cognitive dysfunction. Whether the epilepsy contributes to those, or vice versa, is being addressed in a parallel study.
‘We knew there was something happening that was unique to these kids, but we had no idea what that was,’ said Elliott Sherr, MD, PhD, a UCSF physician-scientist who is the principal investigator of the Epi4K Epileptic Encephalopathy project and who developed this group of patients within EPGP. ‘In a common disease like cystic fibrosis, you’re likely to see more than one child in a family affected. In this case, it is very rare to have more than one person in the entire family with this condition.’
That lack of clear, inherited links to the disease led them to propose that the condition was being caused by de novo, or brand new, mutations on certain genes.
They set out to test that hypothesis.
The team identified children with two classic forms of EE – infantile spasms and Lennox-Gastaut Syndrome – in which no other family member was affected. They excluded children who had identifiable causes of epilepsy, such as strokes at birth, which are a known risk for this group of disorders. Of the 4,000 patients whose genomes are being analysed in the Epi4K, 264 children fit that description.
The Epi4K sequencing team, led by David Goldstein, PhD, at Duke, ran a genetic scan on the children and their parents, which they compared to thousands of people of similar heritage without epilepsy. They used a cutting-edge new technique called exome sequencing to focus on the exome – the 2 percent of our genetic code that represents active, protein-making genes. Those 25,000 genes are considered to be the code for what makes us unique, including disease mutations.
The genetic analysis revealed 439 new mutations in the children, with 181 of the children having at least one. Nine of the genes that hosted those mutations appeared in at least two children with EE and five of those had shown up in previous, smaller EE studies. Of the four others, two may have been coincidental, the researchers found. But two new genes never before associated with EE – known scientifically as GABRB3 and ALG13 – each appeared with less than a one-in-40-billion statistical chance (p = 4.1×10-10) of being connected to EE by coincidence.
The findings implicated GABRB3, for the first time, as a single-gene cause of EE, and offered the strongest evidence to date for the gene’s role in any form of epilepsy, Sherr said. Knowing this about GABRB3, which is also involved with Angelman’s Syndrome, also offers the possibility that children with mutations only in this gene might benefit from the existing therapy for Angelman’s.
Another new gene, ALG13, is key to putting sugars on proteins, which points to a new way of thinking about the causes of and treatment for epilepsy.
‘The take-home is that a lot of these kids have genetic changes that are unique to them,’ Sherr said. ‘Most of these genes have been implicated in these or other epilepsies – others were genes that have never been seen before – but many of the kids have one of these smoking guns.’ University of California – San Francisco

Researchers at the Ruhr-Universität Bochum (RUB) have developed a new spectroscopic method to support pathologists in diagnosing cancer. They compared conventional procedures for colon cancer identification with a novel method called label-free spectral histopathology. ‘Contrary to previous methods we no longer have to stain the tissue in order to detect cancer,’ says Professor Klaus Gerwert from the Protein Research Unit Ruhr within Europe (PURE) at the RUB. ‘In the future, this will give us the opportunity to classify a tissue sample automatically as being either normal or diseased.’
Today pathologists slice tissue obtained from biopsies into thin sections, stain them chemically, and eventually identify colon cancer by visual inspection under the microscope. This is usually done at an advanced stage of the disease, and the method provides no information about the molecular causes of the tumour. However, the method of spectral histopathology (SHP) established at the RUB Department of Biophysics captures molecular alterations directly in the tissues, especially changes of proteins. It works without any labelling agents, such as fluorescent dyes. SHP may even detect alterations occurring in early tumour stages. Since the analysis uses light beams, SHP is not limited to thin sections of biopsy specimens – in fact, one can apply the method directly in live tissue, where it allows to inspect a site of interest with the aid of fibre-optics. ‘In the future, we intend to work together with clinical partners and apply spectral histopathology to patients directly via endoscopes,’ says Klaus Gerwert.
In SHP, researchers record spatially resolved vibration spectra of a tissue using either an infrared or a Raman microscope. A vibration spectrum reflects the condition of all proteins in a tissue at the site measured. Alterations induced by cancer are reflected in the respective spectrum. The spectrum is thus representative of the status of the sample, just like a fingerprint is characteristic of an individual person. Approximately ten million infrared spectra are usually recorded to produce one single tissue image. Using sophisticated computational image analysis procedures, researchers compare these spectra with a reference database. This database contains spectra of already known tissues and tumours, and has been established in the PURE consortium as a collaboration between pathologists, biophysicists and bioinformaticians. The analytical programme allocates each spectrum to tissue types that have been stored in the database, represented by a specific colour—just like an offender who can be identified by comparing his fingerprints with previous database entries. This produces a spatially resolved annotated image of the colon tissue section. Both PURE members, Professor Andrea Tannapfel, Director of the Pathology Institute at the RUB, and Professor Axel Mosig, Head of Bioinformatics at the Department of Biophysics, made the essential contributions in creating the database and the evaluation algorithm. By now, the evaluation programme will run on any commercial laptop. RUB

Knowing what type of lung cancer a patient has is critical to determine which drug will work best and which therapies are safest in the era of personalised medicine. Key to making that judgement is an adequate tumour specimen for the pathologist to determine the tumour’s histology, a molecular description of a tumour based on the appearance of cells under a microscope. But not all specimens are perfect, and are sometimes so complex that a definitive diagnosis presents a challenge.
Scientists at the Universities of North Carolina and Utah have developed a histology expression predictor for the most common types of lung cancer: adenocarcinoma, carcinoid, small cell carcinoma and squamous cell carcinoma. This predictor can confirm histologic diagnosis in routinely collected paraffin samples of patients’ tumours and can complement and corroborate pathologists’ findings.
Neil Hayes, MD, MPH, associate professor of medicine and corresponding author of the study says, ‘As we learn more about the genetics of lung cancer, we can use that understanding to tailor therapies to the individual’s tumour. Gene expression profiling has great potential for improving the accuracy of the histologic diagnosis. Historically, gene expression analysis has required fresh tumour tissue that is usually not possible in routine clinical care. We desperately needed to extend the analysis of genes (aka RNA) to paraffin samples that are routinely generated in clinical care, rather than fresh frozen tissue. That is the major accomplishment of the current study and one of the first large scale endeavours in lung cancer to show this is possible.
‘Our predictor identifies the major histologic types of lung cancer in paraffin-embedded tissue specimens which is immediately useful in confirming the histologic diagnosis in difficult tissue biopsy specimens.’ Dr. Hayes is a member of UNC Lineberger Comprehensive Cancer Center.
The scientists used 442 samples of formalin-fixed paraffin-embedded specimens from lung cancer patients at UNC and the University of Utah Health Sciences Center as they developed their predictor.
First author Matthew Wilkerson, PhD, explains, ‘Our question was, ‘Can histology be predicted accurately by gene expression?’ We had lung cancer genes we already knew were differentially expressed in the different tumour types, so we measured them in tumour paraffin specimens. Next we developed a predictor in an independent set of tumour samples. We then compared the predictor to the actual clinical diagnosis and had additional pathologists review the samples. We showed accuracy as least as good as the pathologist. Our predictor exhibited a mean accuracy of 84 percent, and when compared with pathologist diagnoses, yielded similar accuracy and precision as the pathologists.’

Dr. Hayes summarizes, ‘Going beyond meeting a current need of increasing the accuracy of histologic diagnosis is expected to be the ultimate benefit of this technology. There are many additional characteristics of tumours that could be leveraged for clinical purposes once the world of gene expression analysis from paraffin is efficient from clinical samples. We anticipate additional uses such as predicting responses to additional therapies and prognostication as near term additions.’ University of North Carolina Health Care

Indiana University School of Medicine researchers have found a series of RNA biomarkers in blood that may help identify who is at risk for committing suicide.

The researchers said the biomarkers were found at significantly higher levels in the blood of both bipolar disorder patients with thoughts of suicide as well in a group of people who had committed suicide.

Principal investigator Alexander B. Niculescu III, M.D., Ph.D., associate professor of psychiatry and medical neuroscience at the IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, said he believes the results provide a first ‘proof of principle’ for a test that could provide an early warning of somebody being at higher risk for an impulsive suicide act.

‘Suicide is a big problem in psychiatry. It’s a big problem in the civilian realm, it’s a big problem in the military realm and there are no objective markers,’ said Dr. Niculescu, director of the Laboratory of Neurophenomics at the Institute of Psychiatric Research at the IU School of Medicine.

‘There are people who will not reveal they are having suicidal thoughts when you ask them, who then commit it and there’s nothing you can do about it. We need better ways to identify, intervene and prevent these tragic cases,’ he said.

Over a three-year period, Niculescu and his colleagues followed a large group of patients diagnosed with bipolar disorder, completing interviews and taking blood samples every three to six months. The researchers conducted a variety of analyses of the blood of a subset of participants who reported a dramatic shift from no suicidal thoughts to strong suicidal ideation. They identified differences in gene expression between the ‘low’ and ‘high’ states of suicidal thoughts and subjected those findings to a system of genetic and genomic analysis called Convergent Functional Genomics that identified and prioritized the best markers by cross-validation with other lines of evidence.

The researchers found that the marker SAT1 and a series of other markers provided the strongest biological ‘signal’ associated with suicidal thoughts.

Next, to validate their findings, working with the local coroner’s office, they analysed blood samples from suicide victims and found that some of same top markers were significantly elevated.

Finally, the researchers analysed blood test results from two additional groups of patients and found that high blood levels of the biomarkers were correlated with future suicide-related hospitalisations, as well as hospitalisations that had occurred before the blood tests.

‘This suggests that these markers reflect more than just a current state of high risk, but could be trait markers that correlate with long term risk,’ said Dr. Niculescu.

Although confident in the biomarkers validity, Dr. Niculescu noted that a limitation is that the research subjects were all male.

‘There could be gender differences,’ he said. ‘We would also like to conduct more extensive, normative studies, in the population at large.’

In addition to extending the research to females to see if the same or other markers come into play, Dr. Niculescu and colleagues plan to conduct research among other groups, such as persons who have less impulsive, more deliberate and planned subtypes of suicide. Indiana University School of Medicine