A team of researchers from the United States and the Netherlands has identified mutations in three genes that are associated with high levels of uric acid in the blood, which is a risk factor for gout.  The team developed a genetic risk score composed of the number of uric acid-increasing mutations that each person carries (0 to 6), which was associated with up to a 40-fold increased risk for developing gout when comparing persons at lowest and highest risk.  The findings are published in the October 4 issue of The Lancet.

More than 3 million adults in the United States have gout.  Gout is a painful inflammation of the joints, which can occur with a build-up of uric acid in the blood (hyperuricaemia).  Besides a genetic disposition, obesity, a diet high in meat and cheese, as well as alcohol consumption and certain medications can increase the risk for developing the disease.

The researchers conducted genome-wide association studies of more than 20,000 people enrolled in three large population-based studies investigating cardiovascular disease risk factors: the Framingham Heart Study based at Boston University Medical Center; the Rotterdam Study based at Erasmus Medical Centre in Rotterdam, the Netherlands; and the Atherosclerosis Risk in Communities (ARIC) study based at Johns Hopkins University.  Of more than 500,000 genetic variations that were evaluated, the analysis identified two genes, ABCG2 and SLC17A3, as novel risk genes for gout and confirmed the association of a third gene, SLC2A9.

“This research gives us a better understanding of the underlying causes of gout, which could lead to better prevention and treatment.  Our evidence supports that a common pathway, the handling of uric acid by the kidney, is important in uric acid build-up and therefore for the development of gout,” said study author, Anna Köttgen, MD, MPH, an assistant scientist in the Johns Hopkins Bloomberg School of Public Health’s Department of Epidemiology.

“Genetic risk scores like the one we developed for gout can help alert people at a very early age, well before uric acid levels rise, that they are susceptible to gout.  The new insights are promising for drug development,” said Josef Coresh, MD, PhD, MHS, professor in the Bloomberg School’s departments of Epidemiology and Biostatistics.  “An important unanswered question is whether we can use genetic risk information to motivate people to change their behavior.  For gout, we know that moderate changes in diet and alcohol consumption can lower uric acid levels.  In the future, we will need to test if identification of high-risk individuals can lead to behavior change.”

Many of the seemingly disparate mutations recently discovered in autism may share common underlying mechanisms, say researchers supported in part by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH).  The mutations may disrupt specific genes that are vital to the developing brain, and which are turned on and off by experience-triggered neuronal activity.

A research team led by Christopher Walsh, M.D., Ph.D., and Eric Morrow, M.D., Ph.D., of Harvard University, found two large sections missing on chromosomes in people with autism and traced them to likely inherited mutations in such genes regulated by neuronal activity.  They report their findings in the July 11, 2008 issue of Science.  The study was also supported in part by the NIH’s National Center for Research Resources, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child and Human Development, and the National Institute on Neurological Disorders and Stroke.

The study breaks new ground for complex disorders like autism, taking advantage of a shortcut to genetic discovery by sampling families in which parents are cousins.  The researchers found genes and mutations associated with autism in 88 families from the Middle East, Turkey and Pakistan in which cousins married and had children with the disorder.

“The emerging picture of the genetics of autism is quite surprising.  There appear to be many separate mutations involved, with each family having a different genetic cause,” explained NIMH Director Thomas R. Insel, M.D. “The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”

Earlier studies had suggested that the individually rare mutations are present in at least 10 percent of sporadic cases of autism, which is the most common form.

The researchers used a technique that pinpoints from a relatively small group of families genes responsible for disorders that can be amplified by parenthood among relatives, which can increase transmission of recessive diseases.  Evidence had hinted at such transmission in autism, and the large amount of genetic information obtainable from such families reduced the need for a much larger sample including many families with multiple affected members.

The ratio of females to males with autism – normally one female to four males – was less lopsided in such families in which parents share a common recent ancestor.  This ratio equalized even more in a subset of these families with more than one affected member, suggesting a doubling of the rate of autism, due to recessive causes on non-sex-linked chromosomes.  Also, autism-linked spontaneous deletions and duplications of genetic material were relatively uncommon in these families, suggesting recessive inherited causes.

The researchers found multiple different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry.  Yet a few large inherited autism-linked deletions, likely mutations, in a minority of families stood out.  The largest turned out to be in or near genes regulated, directly or indirectly, by neuronal activity.

“Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child’s experience,” explained Walsh.  “Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity.  Disruption of this refinement process may be a common mechanism of autism-associated mutations.”

What are the genes implicated in upright walking of humans? The discovery of four families in which some members only walk on all fours (quadrupedality) may help us understand how humans, unlike other primates, are able to walk for long periods on only two legs, a scientist will tell the annual conference of the European Society of Human Genetics tomorrow (Monday 2 June).The quadrupedal families in Turkey previously attracted attention in 2005, when they were discovered. Now the Turkish team reports that they have found the first gene implicated in quadrupedal locomotion in these families.

Professor Tayfun Ozcelik, of Bilkent University, Ankara, Turkey, and colleagues, studied four unrelated families where some members were affected by the rare quadrupedic condition, Unertan syndrome, which is also associated with imperfect articulation of speech, mental retardation, and defects in the cerebellum, a part of the brain involved in motor control. They found that the affected individuals in two families had mutations in the gene responsible for the expression of very low density lipoprotein receptor (VLDLR), a protein which is known to be critical to the proper functioning of the cerebellum during development.

Although the families lived in isolated villages 200-300 km apart and reported no ancestral relationships, the scientists expected to find a single genetic mutation implicated in the condition. They were surprised to find that this was not the case.

“We carried out genome-wide screening on these families”, said Professor Ozcelik, “and found regions of DNA that were shared by all those family members who walk on all fours. However, we were surprised to find that genes on three different chromosomes are responsible for the condition in four different families.

“In families A and D there were mutations in VLDLR on chromosome 9, and in family B the phenotype maps to chromosome 17 to a region that contains at least 157 genes, and we are still looking for the precise mutation. Neither region appears to be implicated for family C.”

In all cases, the affected individuals were the offspring of consanguineous marriages, which suggests that if they had married outside the family they would not have had the condition. All of them had significant developmental delay in infancy. “Whereas normal infants make the transition to walking on two legs in a relatively short period”, said Professor Ozcelik, “these individuals continued to move on their palms and feet and never walked upright. Although they can stand from a sitting position and maintain this upright position with flexed hips and knees, they virtually never initiate bipedal walking on their own.”

It has been suggested in the past that lack of access to medical care exacerbated the effects of an under-developed cerebellum, and that this led to quadrupedality. “Although it may be true that family B lacked proper medical care, families A and D had consistent access to good medical attention, and both families sought a correction of quadrupedality in their affected children”, said Professor Ozcelik. “Indeed, an unaffected member of family A is a physician, who has been actively involved in the medical interventions. In addition, the parents in family A also discouraged their affected children from walking on all fours, to no avail. We think that social factors are unlikely to be involved in the development of quadrupedal locomotion.”

Mutations causing VLDLR deficiency are also found in Hutterites, a group of Anabaptists who live in colonies of North America. There, however, most of the affected individuals cannot walk at all. The neurological characteristics of the affected members of the Turkish families and the Hutterites seem similar, with the most striking difference being that the Turkish individuals are able to walk on all fours, said the scientists. They hypothesize that the Hutterites may be more profoundly affected due to the deficiency in VLDLR and a neighbouring gene, and therefore lack the motor skills even for quadrupedal locomotion.

Along with brain enlargement, speech, and the ability to make tools, upright walking has long been regarded as one of the key traits that have led to modern humans. Professor Ozcelik’s team have opened a window on how mutations in VLDLR affect brain development and influence gait in humans.

“It will be interesting to see if the VLDLR gene is involved in other types of cerebellar ataxias. In addition, we hope to identify the defective genes associated with quadrupedal locomotion in families B and C”, he says.

Researchers at the Burnham Institute for Medical Research, led by Josh Luis Millhn, Ph.D., have demonstrated in mice the first successful use of enzyme replacement therapy to prevent hypophosphatasia (HPP), a primary skeletal disease of genetic origin. This discovery lays the foundation for future clinical trials for HPP patients.

Rickets is a softening of the bones that most commonly results from a lack of vitamin D or calcium and from insufficient exposure to sunlight. Hypophosphatasia is a rare, heritable form of rickets caused by mutations in a gene called TNAP, which is essential for the process that causes minerals such as calcium and phosphorus to be deposited in developing bones and teeth. The physical presentations of this disorder can vary depending on the specific mutation, with more severe symptoms occurring at a younger age of onset. The most severe form of the disease occurs at birth, which can present with absence of bone mineralization in utero, resulting in stillbirth.

Using a mouse model, Josh Luis Millhn, Ph.D. tested the hypothesis that, when administered from birth, a bone-targeted form of the TNAP gene would ease the skeletal defects of HPP. The Millhn laboratory, in collaboration with scientists from Enobia Pharma in Montreal, Canada and from the Shriners Hospitals for Children in St. Louis, Missouri, created a soluble form of human TNAP that had been shown to display a strong attraction to bone tissue. Upon injecting the enzyme into the fat layer under the skin of the mice, the treated mice maintained a healthy rate of growth and apparent well being, as well as normal bone mineral density (BMD) of the skull, femur and spine. In fact, complete preservation of skeletal and dental structures were observed after 15 days, and bone lesions were still not seen after 52 days of treatment.

“While the biochemical mechanism that leads to skeletal and dental defects of HPP is now generally understood,” said Dr. Millhn, “there is currently no established medical treatment.”

Given the success of this therapy in preventing HPP, current efforts in Dr. Millhn’s laboratory are focused on reversing the bone defects in mice once the disease is quite advanced. Future clinical trials may reveal this as the first promising therapy for patients with this genetic disorder.

Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations that account for at least 10 percent of the non-familial cases of the disease. Researchers describe specific genetic mutations present in individuals who have schizophrenia, but not present in their biological parents who do not have the disease. These individuals were eight times more likely to have these mutations than unaffected individuals. This new data, reported in the May 30 on-line issue of Nature Genetics, will help researchers account for the persistence of schizophrenia in the population despite low birth rates among people with the disease.Researchers at Columbia University Medical Center scanned the genome of 1,077 people which included 152 individuals with schizophrenia, 159 individuals without schizophrenia, and both of their biological parents for copy number mutations. They found mutations, either a gain or loss of genes, in 15 individuals diagnosed with schizophrenia that were not present in the chromosomes of either biological unaffected parent. Only two of such mutations were found in those without schizophrenia. Study subjects were from the European-origin Afrikaner population in South Africa, a genetically homogenous population that is ideal for genetic evaluation.

“We now know the cause of around 10 percent of the cases of sporadic schizophrenia,” said Maria Karayiorgou, M.D., professor of psychiatry, Columbia University Medical Center, the senior author on the study. “Schizophrenia is not as much of a ‘big black box’ as it used to be. The identification of these genes lets us know what brain development pathways are involved in disease onset, so that in the future we can look at better ways of treating this devastating disease.”

Schizophrenia affects approximately 1 percent of the population worldwide. About 40 percent of the disease is thought to be inherited, with the other 60 percent sporadically showing up in people whose family history does not include the disease.

One of the new or de novo mutations researchers found in more than one affected individual in this study was a deletion of a region of chromosome 22. Dr. Karayiorgou had previously provided evidence that loss of genes in this region, 22q11.2, was responsible for introducing “new” or sporadic cases of schizophrenia in the population. This confirms 22q11.2 as the only known recurrent such mutation linked to schizophrenia.

“We have already demonstrated 22q11.2 to be involved in sporadic schizophrenia and we have made considerable progress in understanding the underlying biological mechanisms,” said Dr. Gogos. “Now, we have a new set of mutations that we can investigate. The more information we have about the biological basis for this disease, the more information we can provide to those who suffer from it and their families.”

“Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism,” explains National Institute of Mental Health Director Thomas R. Insel, M.D. “Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may stem from both hereditary and non-hereditary processes. This line of research holds promise for improved treatments – and perhaps someday even prevention – of developmental brain disorders.”

Karayiorgou and co-senior author Joseph A. Gogos, M.D., Ph.D., associate professor of physiology and neuroscience at Columbia University Medical Center, agree that the goal is for psychiatrists to be able to inform patients that they have a mutation that is causing their disease and ultimately to be able to tailor treatments to individual patients based on their specific mutation. This tailored treatment is a ways off, according to Dr. Karayiorgou, but she says patients and their families are relieved to know that there is a biological cause of their illness.

The researchers plan to extend their screen for additional de novo mutations by using increased resolution scans to study additional families. They also plan to scrutinize further genes affected by the identified mutations through human genetics and animal model approaches.

People with schizophrenia from families with no history of the illness were found to harbor eight times more spontaneous mutations – most in pathways affecting brain development – than healthy controls, in a study supported in part by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH). By contrast, no spontaneous mutations were found in people with schizophrenia who had family histories of the illness.

“Our findings strongly suggest that rare, spontaneous mutations likely contribute to vulnerability in cases of schizophrenia from previously unaffected families,” said Maria Karayiorgou, M.D., of Columbia University, who led the research team. “This may also shed light on why the illness has frustrated efforts to implicate gene variants with major effects, and seems to defy natural selection by persisting in the population even though relatively few of those affected have children.”

Karayiorgou and her colleagues report on their whole genome study online in Nature Genetics, May 30, 2008.

“Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism,” explained NIMH Director Thomas R. Insel, M.D. “Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may not be inherited from parents, at least in the sense that these vulnerabilities were not present in the parental genome. This line of research holds promise for improved treatments – and perhaps someday even prevention – of developmental brain disorders.”

Although it’s known that genetics plays a major role in the transmission of both autism and schizophrenia, most cases are sporadic rather than familial.

Echoing findings of another recent study, Karayiorgou and her colleagues determined that most of the suspect mutations were not random, but found in genes and pathways involved in brain development. However, whether a mutation was spontaneous or inherited was not determined for most of the subjects included in the earlier study.

To pinpoint the sources of the glitches, the researchers in the new study compared genetic data from 369 subjects with data from their biological parents – in a total sample of 1,077 individuals drawn from the European ancestry Afrikaner population in South Africa. Including parental genes makes it possible to definitively determine what’s inherited.

Scans of each person’s genome detected the spontaneous mutations in 15 of 152 individuals (10 percent) with non-familial schizophrenia, and only in two of 159 people (1 percent) without the illness – the eight-fold difference. Such sporadic cases were only 1.5 times more likely than controls to harbor inherited mutations.

The researchers also found three deletions of genetic material at a site on chromosome 22 previously implicated in schizophrenia, confirming it as the only known recurrent such mutation linked to schizophrenia.