By
Gonca Bumin
J Rehabil Med 2003; 35: 44–45
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Thursday, January 28, 2010
Wednesday, January 27, 2010
Variants in synaptic protein linked to autism
Scientists have identified several autism-specific variants in a gene that lies within a chromosomal region linked to the disorder, according to a poster presented at the World Congress of Psychiatric Genetics in San Diego.
Interestingly, a closer look at one family tree suggests that some of these variants may be harmless when carried alone but, when inherited together, may lead to autism. The results are in press at the journal Autism Research.
Last year, Susan Christian and colleagues at the University of Chicago found a large, inherited DNA duplication in chromosomal region 15q13.1 shared by two brothers with autism1. The region — which has also been linked to schizophrenia, mental retardation and epilepsy — includes a gene called APBA2 that encodes a protein at the synapse, the nexus of neuronal communication.
A few months earlier, a different research group had found the same duplication in an individual with schizophrenia. That study also identified another individual with schizophrenia who is missing a segment on chromosome 2, disrupting neurexin 1, a synaptic protein that interacts with APBA22.
Because the APBA2 and NRXN1 proteins interact at the synapse, these variants are particularly good candidates for understanding what causes autism, says Ravinesh Kumar, Christian's collaborator and a postdoctoral fellow in William Dobyns' lab at the University of Chicago.
Several studies have linked NRXN1 and closely related genes to autism, prompting the researchers to investigate whether APBA2 mutations also crop up in people with the disorder. Mouse studies have shown that animals lacking the gene display abnormal social behaviors3.
"It might be that having the duplication, too much of the gene, might contribute to autism in some regard. But a mutation that disrupts the function of a gene might have a completely different effect," Kumar says. "It's really tricky to try to interpret."
Kumar sequenced the protein-coding regions of APBA2 in people with autism and in healthy controls. He drew the autism samples from the Autism Genetic Resource Exchange, a large gene bank of children with autism and their families.
Analyzing 512 blood samples from people with autism and 463 healthy controls, Kumar found seven novel rare APBA2 variants that are unique to the autism group, and four APBA2 variants specific to the control group. The difference is not great enough to say with statistical confidence that the variants are more common in autism.
One family in the autism group has a particularly interesting family tree, however. Two brothers, both diagnosed with autism, each carry the same two APBA2 variants. Their mother carries one of the variants, and their father the other, but neither parent has autism.
"Our hypothesis is that one event is not sufficient to give rise to autism, but having both is sufficient," Kumar says. "But at this point, it's still speculative."
Taken together with older studies, the results suggest that APBA2 is a good candidate gene for autism, he says, and deserves further study.
References:
Christian S.L. et al. Biol. Psychiatry 63, 1111-1117 (2008) PubMed
Kirov G. et al. Hum. Mol. Genet. 17, 458-465 (2008) PubMed
Sano Y. et al. J. Neurosci. 29, 5884-5896 (2009) PubMed
Interestingly, a closer look at one family tree suggests that some of these variants may be harmless when carried alone but, when inherited together, may lead to autism. The results are in press at the journal Autism Research.
Last year, Susan Christian and colleagues at the University of Chicago found a large, inherited DNA duplication in chromosomal region 15q13.1 shared by two brothers with autism1. The region — which has also been linked to schizophrenia, mental retardation and epilepsy — includes a gene called APBA2 that encodes a protein at the synapse, the nexus of neuronal communication.
A few months earlier, a different research group had found the same duplication in an individual with schizophrenia. That study also identified another individual with schizophrenia who is missing a segment on chromosome 2, disrupting neurexin 1, a synaptic protein that interacts with APBA22.
Because the APBA2 and NRXN1 proteins interact at the synapse, these variants are particularly good candidates for understanding what causes autism, says Ravinesh Kumar, Christian's collaborator and a postdoctoral fellow in William Dobyns' lab at the University of Chicago.
Several studies have linked NRXN1 and closely related genes to autism, prompting the researchers to investigate whether APBA2 mutations also crop up in people with the disorder. Mouse studies have shown that animals lacking the gene display abnormal social behaviors3.
"It might be that having the duplication, too much of the gene, might contribute to autism in some regard. But a mutation that disrupts the function of a gene might have a completely different effect," Kumar says. "It's really tricky to try to interpret."
Kumar sequenced the protein-coding regions of APBA2 in people with autism and in healthy controls. He drew the autism samples from the Autism Genetic Resource Exchange, a large gene bank of children with autism and their families.
Analyzing 512 blood samples from people with autism and 463 healthy controls, Kumar found seven novel rare APBA2 variants that are unique to the autism group, and four APBA2 variants specific to the control group. The difference is not great enough to say with statistical confidence that the variants are more common in autism.
One family in the autism group has a particularly interesting family tree, however. Two brothers, both diagnosed with autism, each carry the same two APBA2 variants. Their mother carries one of the variants, and their father the other, but neither parent has autism.
"Our hypothesis is that one event is not sufficient to give rise to autism, but having both is sufficient," Kumar says. "But at this point, it's still speculative."
Taken together with older studies, the results suggest that APBA2 is a good candidate gene for autism, he says, and deserves further study.
References:
Christian S.L. et al. Biol. Psychiatry 63, 1111-1117 (2008) PubMed
Kirov G. et al. Hum. Mol. Genet. 17, 458-465 (2008) PubMed
Sano Y. et al. J. Neurosci. 29, 5884-5896 (2009) PubMed
Miracle of Brain Wave Vibration therapy in Rett syndrome: Video
Story of Annette: A Rett angel
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Stem Cell Debate: Video 1
Doctor Shocks Oprah with News of Ethical Stem-Cell Successes
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Enriched environment improves symptoms of Rett
Kelly Rae Chi
Oct, 2009
Giving mouse models of Rett syndrome access to toys, wheels and contact with other mice rescues motor skill and other deficits characteristic of the disorder, according to results presented in a poster session Wednesday at the Society for Neuroscience meeting in Chicago.
Rett syndrome, which occurs mostly in girls, is marked by an apparently normal infancy, followed by a progressive deterioration of motor, social and intellectual skills beginning in early childhood. Children with Rett syndrome often show autism-like behaviors in the syndrome's early stages.
A decade ago, researchers discovered that mutations in the MECP2 gene lead to Rett syndrome and, in 2002, scientists created the first mouse model of the disorder.
Exposing Rett mouse models to an enriched environment has, in previous studies, produced mixed results. For example, in a study published last year, researchers gave mice access to toys, wheels and other mice starting at 4 weeks of age, shortly after being weaned from their mothers. The researchers found that the enriched setting improves motor skills in female mice, but not in males1.
Levels of brain-derived neurotrophic factor, or BDNF — a gene target of MECP2 that's thought to be important for learning and memory — does not increase in the male mutant mice but does in the females.
To investigate the benefits of an even earlier intervention, scientists gave Rett mice access to tubes and wheels, and to other mice, including their mothers, beginning at 10 days after birth.
At 30 days, mutant mice in the enriched environment have better motor skills than those kept in standard cages, and they learn tasks as easily as normal mice do. The intervention also ups BDNF levels, but not quite to the level of control mice in the enriched setting, the researchers found.
"In our hands, it worked. Starting early is key," says lead investigator Maurizio Giustetto, a professor of anatomy at the University of Torino in Italy. His group collaborated with Tommaso Pizzorusso of the Consiglio Nazionale delle Ricerche in Italy.
Using high-resolution microscopy, the group looked closely at synapses, the connections between neurons, to asses the proportion of excitatory synapses to inhibitory ones. An imbalance between the two kinds is thought to underlie Rett syndrome and autism.
Mutants given enriched settings have higher numbers of excitatory synapses compared with untreated mutants, the team found; the number of inhibitory synapses does not change. Analyzing the electrical activity of neurons, the group also found that enrichment improves the strength of the connections between neurons, a process important for learning and memory.
The group has thus far analyzed brain slices in a dish, but they plan to develop methods to examine the cells and circuits in whole animals.
References:
Kondo M. et al. Eur. J. Neurosci. 27, 3342-3350 (2008) PubMed
Note: Click on the title to read the Full article
Oct, 2009
Giving mouse models of Rett syndrome access to toys, wheels and contact with other mice rescues motor skill and other deficits characteristic of the disorder, according to results presented in a poster session Wednesday at the Society for Neuroscience meeting in Chicago.
Rett syndrome, which occurs mostly in girls, is marked by an apparently normal infancy, followed by a progressive deterioration of motor, social and intellectual skills beginning in early childhood. Children with Rett syndrome often show autism-like behaviors in the syndrome's early stages.
A decade ago, researchers discovered that mutations in the MECP2 gene lead to Rett syndrome and, in 2002, scientists created the first mouse model of the disorder.
Exposing Rett mouse models to an enriched environment has, in previous studies, produced mixed results. For example, in a study published last year, researchers gave mice access to toys, wheels and other mice starting at 4 weeks of age, shortly after being weaned from their mothers. The researchers found that the enriched setting improves motor skills in female mice, but not in males1.
Levels of brain-derived neurotrophic factor, or BDNF — a gene target of MECP2 that's thought to be important for learning and memory — does not increase in the male mutant mice but does in the females.
To investigate the benefits of an even earlier intervention, scientists gave Rett mice access to tubes and wheels, and to other mice, including their mothers, beginning at 10 days after birth.
At 30 days, mutant mice in the enriched environment have better motor skills than those kept in standard cages, and they learn tasks as easily as normal mice do. The intervention also ups BDNF levels, but not quite to the level of control mice in the enriched setting, the researchers found.
"In our hands, it worked. Starting early is key," says lead investigator Maurizio Giustetto, a professor of anatomy at the University of Torino in Italy. His group collaborated with Tommaso Pizzorusso of the Consiglio Nazionale delle Ricerche in Italy.
Using high-resolution microscopy, the group looked closely at synapses, the connections between neurons, to asses the proportion of excitatory synapses to inhibitory ones. An imbalance between the two kinds is thought to underlie Rett syndrome and autism.
Mutants given enriched settings have higher numbers of excitatory synapses compared with untreated mutants, the team found; the number of inhibitory synapses does not change. Analyzing the electrical activity of neurons, the group also found that enrichment improves the strength of the connections between neurons, a process important for learning and memory.
The group has thus far analyzed brain slices in a dish, but they plan to develop methods to examine the cells and circuits in whole animals.
References:
Kondo M. et al. Eur. J. Neurosci. 27, 3342-3350 (2008) PubMed
Note: Click on the title to read the Full article
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