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Home | Pregnancy Timeline | News Alerts |News Archive Feb 20, 2015

This is a five-month-old baby girl diagnosed with Angelman Syndrome.
Image Credit: Vanderbilt University




Angelman Syndrome and our Circadian clocks

Monitoring a childs' biological clocks may be the quickest way to determine the effectiveness of experimental drugs currently under development to treat Angelman syndrome — a debilitating genetic disorder that occurs in more than one of every 15,000 live births.

That is one of the implications of a study published in the journal Current Biology, which establishes a molecular link between a slow-down in the biological clock in the brains of an AS individual and the genetic deficits that cause the condition. Currently, there is no way to treat AS, which delays brain development and causes lack of speech, seizures, walking and balance problems and sleep disorders. In the last five years, however, scientists have found two approaches that hold considerable promise that will soon be undergoing clinical trials.

"One of the problems with assessing the effectiveness of treatments for AS is that it might take years for the improvements to become apparent," said co-author Terry Jo Bichell, the doctoral student at Vanderbilt University who performed the pilot studies of the relationship between AS and Circadian rhythm. "However, the slower biological clock in Angelman syndrome could provide the quickest way to prove that a treatment is working. Normalization of the core circadian rhythms of AS subjects would be a great biomarker for experimental medications."

Angelman Syndrome, which is often misdiagnosed as cerebral palsy or autism, is caused when the maternal copy of a specific gene, UBE3A located on chromosome 15, is missing or damaged.

"This gene plays an important role in regulating the concentration of the enzyme 'ubiquitin ligase' during development. Ubiquitin ligase, in turn, regulates a number of other proteins. When the concentration is too high, it can lead to autism, but if it is too low, it can cause Angelman syndrome."

Carl Johnson, Stevenson Professor of Biological Sciences and senior author on the study.

Normally, an individual has both a maternal and a paternal copy of UBE3A. However, only the maternal copy is expressed in the brain. The paternal gene is silenced. The majority of AS cases (68 percent) are caused by a "big deletion" or where a big chunk of DNA including UBE3A is missing from the maternal copy of chromosome 15. Another 11 percent of the cases are due to point mutations that inactivate the gene and 7 percent occur in individuals carrying two copies of the paternal gene. The remainder are experiencing a mixture of several other causes.

The promising experimental treatments approaching the stage of clinical trials involve activating the paternal copy of UBE3A in the brain. One treatment uses Topotecan, a cancer chemotherapy agent. Another, uses a small DNA analog that unsilences the paternal AS gene — and is known as an antisense oligonucleotide.

"This is very exciting," said Bichell, whose son has AS. "Fifteen years ago when our son was diagnosed with AS there were no treatments. There weren't even any clinical trials."

Serious sleep disorders are one of the symptoms of AS. These can be so serious that children must sleep in special crib-like beds to keep them from wandering or harming themselves at night.

The Vanderbilt researchers used two strains of mice that exhibited the symptoms of AS. One had the equivalent of the "big deletion" and the other had a point mutation in UBE3A. The researchers determined that the biological clocks of both strains ran significantly slower than normal. They also found that their biological clocks were not robust as is needed and were more easily influenced by environmental conditions. These characteristics may account for the sleep disorders AS patients suffer.

"In many cases, animal models do not recapitulate the clinical features of major mental disorders. But AS is an exception. Angelman Syndrome is caused primarily by a loss of function of a single gene and the mouse models we used mimic many of the symptoms found in human patients. Of course, we must be cautious when we try to apply the results of these studies to humans."

Shuqun Shi PhD, professor and research assistant.

"If we can just find a treatment that allows AS patients to sleep soundly, it would be very worthwhile," said Bichell. "Dealing with sleep disorders can be one of the most stressful aspects of raising a child with AS."

The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS.

We found a unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS-model mice, indicating an important role for Ube3a in modulating BMAL1 turnover.

Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients.

The research was supported by National Heart, Lung and Blood Institute grant R21HL102492-01A1, National Institute of General Medical Sciences grant R01GM088595, National Institute of Diabetes and Digestive and Kidney Diseases U24DK076169 and the Brain & Behavior Research Foundation Young Investigator Award #17623.

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