Category Archives: Transhuman News

Among the problems people with Autism spectrum disorders (ASD) struggle with are difficulties with social behavior and communication. That can translate to an inability to make friends, engage in routine conversations, or pick up on the social cues that are second nature to most people. Similarly, in a mouse model of ASD, the animals, like humans, show little interest in interacting or socializing with other mice.

One drug, risperidone, works in both humans and mice with ASD to treat other symptoms of the disorder -- including repetitive behaviors--but no medication has been found to help socialization.

Now researchers at UCLA have treated ASD mice with a neuropeptide--molecules used by neurons to communicate with each other--called oxytocin, and have found that it restores normal social behavior. In addition, the findings suggest that giving oxytocin as early as possible in the animal's life leads to more lasting effects in adults and adolescents. This suggests there may be critical times for treatment that are better than others.

The study appears in the January 21 online edition of the journal Science Translational Medicine.

Mouse models of neuropsychiatric diseases provide a platform for understanding the mechanisms behind disorders and development of new therapies, noted Daniel Geschwind, a UCLA professor of psychiatry, neurology and human genetics, and senior author of the study. In 2011, Geschwind and his colleagues developed a mouse model for ASD by knocking out a gene called CNTNAP2 (contactin-associated protein-like 2), which scientists believe plays an important role in the brain circuits responsible for language and speech. Previous research has linked common CNTNAP2 variants to heightened autism risk in the general population, while rare variants can lead to an inherited form of autism called cortical dysplasia-focal epilepsy syndrome (CDFE).

It's known that the oxytocin is involved in regulating various aspects of social behavior. Among its other roles, oxytocin neurons in the brain's hypothalamus interact with several other brain regions, including the amygdala, hippocampus, and frontal cortex, where they influence such behaviors as fear, memory, and social behavior.

"The oxytocin system is a key mediator of social behavior in mammals, including humans, for maternal behavior, mother-infant bonding, and social memory," said Geschwind, who holds UCLA's Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and is the director of the Center for Autism Research and Treatment at the Semel Institute for Neuroscience and Human Behavior at UCLA. "So it seemed like a natural target for us to go after."

In the ASD mice, the researchers found a decrease in the number of oxytocin neurons in the hypothalamus and, overall, a decrease in oxytocin levels throughout the brain. But when they administered oxytocin to the ASD mice, sociability, defined as time spent interacting normally with other mice, was restored. Then, using a second strategy, the researchers also found that by giving the mice melanocortin, an agonist (which binds to specific receptors on a cell to activate it) caused a natural release of oxytocin from brain cells, which also improved social deficits.

"The study shows that a primary deficit in oxytocin may cause the social problems in these mice, and that correcting this deficit can correct social behavior," said Geschwind. "We were surprised as well to discover a relationship between the cntnap2 protein and oxytocin--the absence of cntnap2 effected oxytocin neurons in the hypothalamus."

The biggest surprise, though, said Geschwind, was finding that early postnatal administration of the oxytocin led to longer positive effects upon social behavior when measured several weeks later. "This suggests that there may be critical windows of time for treatment that are better than others."

Originally posted here:
Treatment restores sociability in autism mouse model

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Newswise BIRMINGHAM, Ala. An international group co-led by University of Alabama at Birmingham researcher Mary MacDougall, Ph.D., has unraveled the molecular basis for the rare, inherited genetic disorder, Singleton-Merten Syndrome (SMS). Individuals with SMS develop extreme, life-threatening calcification of the aorta and heart valves, early-onset periodontitis and root resorption of the teeth, decreases in bone density, and loss of bone tissue at the tips of fingers and toes.

The cause of SMS is a missense mutation that changes a single amino acid in the protein MDA5 from arginine to glutamine, MacDougall and colleagues are reporting today (Jan. 22) in the online version of The American Journal of Human Genetics. That change in MDA5 which detects viral double-stranded RNA as part of the innate immunity system causes increased induction of interferon beta. Thus SMS is recognized as an innate autoimmune disease for the first time.

The autoimmunity finding was startling, said MacDougall, associate dean for research, James R. Rosen Chair of Dental Research, and professor in the Department of Oral and Maxillofacial Surgery at the UAB School of Dentistry, and director of UABs Global Center for Craniofacial, Oral and Dental Disorders. She and Frank Rutsch, M.D., Department of General Pediatrics, Muenster University Childrens Hospital, Germany, are co-first authors of the paper, A Specific IFIH1 Gain-of-function Mutation Causes Singleton-Merten Syndrome.

Because of the unusual dental problems in SMS patients, Rutsch had contacted MacDougall 10 years ago to probe the molecular mechanisms of the syndrome. MacDougall is an internationally respected research leader in craniofacial developmental biology and dental genetics, particularly the molecular basis and mechanisms associated with human dental genetic disorders that alter tooth number, formation and hard tissue structure. Such investigations of differentiation during tooth and bone formation have broad applications across medical research.

SMS is an autosomal-dominant disorder, meaning the mutation is not carried on the sex chromosomes, and a single copy of the mutation in the gene IFIH1 that encodes MDA5 can cause disease. Rutsch identified three SMS-affected families, and researchers in Cologne, Germany performed whole-exome DNA sequencing and targeted Sanger sequencing to identify the mutation. The same mutation was found in 10 different patients.

MacDougalls group at UAB analyzed the dental features of patients and created cell lines from SMS individuals and controls. Several of the dental pulp cell lines came from an extracted, forming third-molar that was shipped from Germany to Alabama by FedEx.

Functional studies by the UAB group found that: MDA5 as measured by immunohistochemistry of human heart, skin and cartilage tissue, or demineralized developing mouse teeth was present in all target tissues that are altered in SMS. Presence of the SMS- IFIH1 mutant gene increased interferon beta gene expression by 20-fold, and correcting the single mutation of the SMS-IFIH1 back to normal reduced expression to control levels. The SMS- IFIH1 mutant gene had a greater response, as measured by interferon beta induction, when challenged with double-stranded RNA, as compared with the normal gene. Whole blood of SMS individuals and the cell lines developed from the SMS tooth had higher expression of interferon signature genes, compared with control individuals and cells.

Thus, the altered gene is a gain-of-function mutation. Recently, IFIH1 has been linked to several autoimmune disorders, including Aicardi-Goutieres syndrome, though those individuals show brain and developmental defects.

Original post:
UAB Research Probes Molecular Basis of Rare Genetic Disorder

An international group co-led by University of Alabama at Birmingham researcher Mary MacDougall, Ph.D., has unraveled the molecular basis for the rare, inherited genetic disorder, Singleton-Merten Syndrome (SMS). Individuals with SMS develop extreme, life-threatening calcification of the aorta and heart valves, early-onset periodontitis and root resorption of the teeth, decreases in bone density, and loss of bone tissue at the tips of fingers and toes.

The cause of SMS is a missense mutation that changes a single amino acid in the protein MDA5 from arginine to glutamine, MacDougall and colleagues are reporting today (Jan. 22) in the online version of The American Journal of Human Genetics. That change in MDA5 -- which detects viral double-stranded RNA as part of the innate immunity system -- causes increased induction of interferon beta. Thus SMS is recognized as an innate autoimmune disease for the first time.

"The autoimmunity finding was startling," said MacDougall, associate dean for research, James R. Rosen Chair of Dental Research, and professor in the Department of Oral and Maxillofacial Surgery at the UAB School of Dentistry, and director of UAB's Global Center for Craniofacial, Oral and Dental Disorders. She and Frank Rutsch, M.D., Department of General Pediatrics, Muenster University Children's Hospital, Germany, are co-first authors of the paper, "A Specific IFIH1 Gain-of-function Mutation Causes Singleton-Merten Syndrome.

Because of the unusual dental problems in SMS patients, Rutsch had contacted MacDougall 10 years ago to probe the molecular mechanisms of the syndrome. MacDougall is an internationally respected research leader in craniofacial developmental biology and dental genetics, particularly the molecular basis and mechanisms associated with human dental genetic disorders that alter tooth number, formation and hard tissue structure. Such investigations of differentiation during tooth and bone formation have broad applications across medical research.

SMS is an autosomal-dominant disorder, meaning the mutation is not carried on the sex chromosomes, and a single copy of the mutation in the gene IFIH1 that encodes MDA5 can cause disease. Rutsch identified three SMS-affected families, and researchers in Cologne, Germany performed whole-exome DNA sequencing and targeted Sanger sequencing to identify the mutation. The same mutation was found in 10 different patients.

MacDougall's group at UAB analyzed the dental features of patients and created cell lines from SMS individuals and controls. Several of the dental pulp cell lines came from an extracted, forming third-molar that was shipped from Germany to Alabama by FedEx.

Functional studies by the UAB group found that: MDA5 -- as measured by immunohistochemistry of human heart, skin and cartilage tissue, or demineralized developing mouse teeth -- was present in all target tissues that are altered in SMS. Presence of the SMS- IFIH1 mutant gene increased interferon beta gene expression by 20-fold, and correcting the single mutation of the SMS-IFIH1 back to normal reduced expression to control levels. The SMS- IFIH1 mutant gene had a greater response, as measured by interferon beta induction, when challenged with double-stranded RNA, as compared with the normal gene. Whole blood of SMS individuals and the cell lines developed from the SMS tooth had higher expression of interferon signature genes, compared with control individuals and cells.

Thus, the altered gene is a gain-of-function mutation. Recently, IFIH1 has been linked to several autoimmune disorders, including Aicardi-Goutieres syndrome, though those individuals show brain and developmental defects.

The UAB research team included Changming Lu and Olga Mamaeva, research associates for the Institute of Oral Health Research in the UAB School of Dentistry, and Heidi Erlandsen, a former dental school instructor.

MacDougall is continuing SMS gene research at UAB, including probing the impact of its dysregulation of 30 genes that are involved in tooth formation and dentin mineralization; using it as a paradigm for patients with other diseases, such as periodontitis and aggressive periodontitis; screening glaucoma patients for the mutation, since early-onset glaucoma is one phenotype seen in some SMS individuals; and looking for altered microbiomes and oral biomes in SMS individuals.

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Research probes molecular basis of rare genetic disorder