Posts tagged X chromosome
Articles and news from the latest research reports.
(Image caption: These scans show atrophy of the cerebellum in a boy with Christianson Syndrome. This symptom was observed in some, but not all boys, with the condition. Credit: Eric Morrow/Brown University)
Diagnostic criteria for Christianson Syndrome
Because the severe autism-like condition Christianson Syndrome was only first reported in 1999 and some symptoms take more than a decade to appear, families and doctors urgently need fundamental information about it. A new study that doubles the number of cases now documented in the scientific literature provides the most definitive characterization of CS to date. The authors therefore propose the first diagnostic criteria for the condition.
"We’re hoping that clinicians will use these criteria and that there will be more awareness among clinicians and the community about Christianson Syndrome," said Brown University biology and psychiatry Assistant Professor Dr. Eric Morrow, senior author of the study in press in the Annals of Neurology. “We’re also hoping this study will impart an opportunity for families to predict what to expect for their child and what’s a part of the syndrome.”
In conducting their study, which includes detailed behavioral, medical and genetic observations of 14 boys with CS from 12 families, the team of scientists and physicians worked closely with families of the small but fast-growing Christianson Syndrome Association , including hosting the group’s inaugural conference at Brown’s Alpert Medical School last summer.
In their study, Morrow’s team was able to quantify the most frequent symptoms specific to CS. These include moderate to severe intellectual disability, epilepsy, difficulty or inability walking and talking, attenuated head and brain growth, and hyperactivity. Boys sometimes exhibit other specific symptoms – including autism-like behaviors, low height and weight, acid reflux, and regressions in speech and motor skills after age 10 – that the researchers include as secondary proposed diagnostic criteria. A third of the boys also had potentially neurodegenerative problems such as atrophy of the cerebellum.
What’s still not clear is whether the disease limits the eventual lifespan of patients.
Distinct genetic cause
Many CS traits, including a very happy disposition, appear similar to those of another autism-like condition, Angelman Syndrome, but the study defines important differences.
Among the most important ones is that the two syndromes have distinct genetic underpinnings. In all CS cases, said Morrow who treats autism patients at the E. P. Bradley Hospital in East Providence, boys have a mutation on the SLC9A6 gene on the X chromosome that disables production of a protein called NHE6 that is important for neurological development.
Girls, who have two X chromosomes, can also be carriers of CS mutations, but they appear to be affected differently and less severely or not at all, the study reports.
The connection to the SLC9A6 gene was first discovered in 2008. In analyzing the genomes of each patient and their parents in the new study, lead authors Matthew Pescosolido, a graduate student, and David Stein, a former undergraduate, found that each boy had only one mutation, but there were many different ones across the entire group. More often than not, they determined, the mutation was not inherited, but an unlucky “de novo” change that occurred in the affected boy. In two situations, boys in unrelated families happened to share the same mutation. These recurrent mutations suggest that there may be hotspots in the DNA for mutation at these sites, Morrow said, although further research will be necessary to sort this out.
Morrow said there is evidence that SLC9A6 mutations – and therefore CS – may be a relatively common source of X-linked intellectual disability. One study, for example found that SLC9A6 mutations in two of 200 people suspected of having X-linked ID. Another found that 1 in 19 families with a case of ID exhibited a mutation that truncated the NHE6 protein.
"If we assume that between 1-3 percent of the world’s population is diagnosed with an intellectual disability and approximately 10-20 percent of the causes are due to X-linked genes, then we can estimate that CS may affect between 1 in 16,000 to 100,000 people," Morrow and his co-authors wrote. Worldwide that frequency would add up to more than 70,000 cases.
Relevance to autism, epilepsy
In a paper published last year, Morrow’s research group found that NHE6 is underexpressed in the brains of many children with more general forms of autism. This potential connection suggests that learning about CS can help doctors and scientists learn about autism.
Similarly by studying the regression of walking and verbal skills among Christianson boys, Morrow said researchers could learn more about regressions in autism.
"Christianson syndrome, I hope will be a model," Morrow said. "If we could understand the biological mechanism that leads to that loss, and we can prevent it, by developing a treatment, then these kids will remain further ahead."
Such advances will require much more study, but Morrow said that by uncovering a variety of mutations that all lead to the disease, the study provides a wealth of new information for that work.
"We can now study these different mutations and learn how this protein works by how it gets inactivated," he said. "All the different ways it gets inactivated can actually inform us about the different components of the protein that have an important function."
Neuroscientists explain how mutated X-linked mental retardation protein impairs neuronal function
There are new clues about malfunctions in brain cells that contribute to intellectual disability and possibly other developmental brain disorders.
(Image caption: False color image of a mouse hippocampal neuron (cell
body is at lower right) with branchlike dendrites that provide surfaces at which projections from other neurons can connect, by forming synapses. Van Aelst and colleagues have shown that when the OPHN1 protein is mutated, interfering with its ability to interact with another protein called Homer1b/c, AMPA receptors don’t recycle to the surface at synapses at the rate they normally do. This adversely impacts synaptic plasticity, the process by which neurons adjust the strength of their connections. Such pathology may play a role in X-linked mental retardation.)
Professor Linda Van Aelst of Cold Spring Harbor Laboratory (CSHL) has been scrutinizing how the normal version of a protein called OPHN1 helps enable excitatory nerve transmission in the brain, particularly at nerve-cell docking ports containing AMPA receptors (AMPARs). Her team’s new work, published June 24 in the Journal of Neuroscience, provides new mechanistic insight into how OPHN1 defects can lead to impairments in the maturation and adjustment of synaptic strength of AMPAR-expressing neurons, which are ubiquitous in the brain and respond to the excitatory neurotransmitter glutamate.
Mutations in a gene called oligophrenin-1 (OPHN1) – located on the X chromosome – have previously been linked to X-linked intellectual disability (also known as X-linked mental retardation), a condition that affects boys disproportionately and could account for as much as one-fifth of all intellectual disability among males.
Several different mutations in the OPHN1 gene have been identified to date, all of which perturb nerve cells’ manufacture of OPHN1 protein. Previously, Van Aelst and colleagues demonstrated that OPHN1 has a vital role in synaptic plasticity, the process through which adjacent nerve cells adjust the strength of their connections. Cells in the brain are constantly adjusting connection strength as they respond to streams of stimuli.
The new discovery shows how OPHN1 is involved in the trafficking of AMPARs, an essential feature of plasticity in neurons. Neurons move receptors away from synapses into their interior and then back to the surface of synapses to control connection strength. At the synaptic surface, receptors provide an opportunity for the docking of neurotransmitters, in this case glutamate molecules. After a cell has fired, surface receptors are typically brought back into the interior, where they are recycled for future use.
When OPHN1 is misshapen or missing due to genetic mutation, the CSHL team demonstrated, it can no longer properly perform its role in receptor recycling, thus also impairing neurons’ ability to maintain strong long-term connections with their neighbors, called long-term potentiation.
Van Aelst’s new experiments explain how OPHN1 in complex with another protein called Homer1b/c should normally interact with an area called the endocytic zone (EZ) to provide a pool of AMPARs to be brought to the synapse at a location called the post-synaptic density (PSD). When OPHN1 is mutated, the pool does not form and receptors needed for strengthening synapses are not available. Long-term potentiation is impaired.
“This suggests a previously unknown way in which genetic defects in OPHN1 can lead to dysfunctions in the glutamate system,” says Dr. Van Aelst. “Our earlier studies had already shown that OPHN1 is essential in stabilizing AMPA receptors at the synapse. Together, these two essential roles suggest how defective OPHN1 protein may contribute to pathology that underlies X-linked intellectual disability.”
(Source: cshl.edu)
Color-Coded Cells Reveal Patchwork Patterns of X Chromosome Silencing in Female Brains
Producing brightly speckled red and green snapshots of many different tissues, Johns Hopkins researchers have color-coded cells in female mice to display which of their two X chromosomes has been made inactive, or “silenced.”
(Image caption: Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice (clockwise). Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. Hao Wu, courtesy of Neuron)
Scientists have long known that the silencing of one X chromosome in females — who have two X chromosomes in every cell — is a normal occurrence whose consequences can be significant, especially if one X chromosome carries a normal copy of a gene and the other X chromosome carries a mutated copy.
By genetically tagging different X chromosomes with genes that code for red or green fluorescent proteins, scientists say they can now peer into different tissue types to analyze genetic diversity within and between individual females at a new level of detail.
Published on Jan. 8 in the journal Neuron, a summary of the research shows wide-ranging variation in patterns of so-called X chromosome inactivation at every level: within tissues, on the left or right sides of a centrally located tissue (like the brain), among different tissue types, between paired organs (like the eyes) and among individuals.
"Calico cats, which are only ever female, have mottled coat colors. They have two different versions of a gene for coat color, which is located on the X chromosome: one version from their mother and the other from their father," explains Jeremy Nathans, M.D., Ph.D., professor of molecular biology and genetics at the Johns Hopkins University and a Howard Hughes Medical Institute investigator. "Their fur is orange or black depending on which X chromosome is silenced in a particular patch of skin cells. X chromosome inactivation actually occurs in all cells in female mammals, including humans, and it affects most of the genes on the X chromosome. Although this phenomenon has been known for over 50 years, it couldn’t be clearly visualized in internal organs and tissues until now."
Nathans adds that early in the development of most mammals, when a female embryo has only about 1,000 cells, each cell makes a “decision” to inactivate one of the two X chromosomes, a process that silences most of the genes on that chromosome. The choice of which X chromosome to inactivate appears to be random, but when those cells divide, their descendants maintain that initial decision.
In the new research, the Johns Hopkins team mated female mice carrying two copies of the gene for green fluorescent protein — one on each of the two X chromosomes — with male mice whose single X chromosome carried the gene for a red fluorescent protein. The female offspring from this mating had cells that glowed red or green based on which X chromosome was silenced. Additionally, the team engineered the mice so that not all of their cells were color-coded, since that would make it hard to distinguish one cell from another. Instead, they designed a system that allowed a single cell type in each mouse, such as heart muscle cells, to be color-coded. Their genetic trick resulted in red and green color maps with distinctive patterns for each cell and tissue type that they examined.
Nathans explains that the patterns are determined by the way each tissue develops. Some tissues are created from a very small number of “founder cells” in the early embryo; others are created from a large number. Statistically, the larger the group of founder cells, the greater the chances are of having a nearly equivalent number of red and green cells. Although the ratio in the founding group is roughly preserved as the tissue grows, the distribution of those cells is determined by how much movement occurs during the development of the tissue. For example, in a tissue like blood, where the cells move a lot, the red and green cells are finely intermingled. By contrast, in skin, where the cells show little movement, each patch of skin consists of the descendants of a single cell, which share the same inactive X chromosome — and therefore the same color — creating a coarse patchwork of red and green.
Normally, the pattern of X chromosome inactivation is not easily visualized. This color-coding technique is likely to be valuable for many studies, Nathans says, especially for research on variations caused by changes in the DNA sequence of the X chromosome, referred to as X-linked variation. X-linked genetic variations, such as hemophilia or color blindness, are relatively common, in part because the X chromosome carries many genes — approximately 1,000, or close to 4 percent of the total.
Males who inherit an X-linked disease usually suffer its effects because they have no second X chromosome to compensate for the mutant version of the gene. Female relatives, on the other hand, are more typically “carriers” of X-linked diseases. They have the ability to pass the disease along to their male progeny, but they do not suffer from it themselves due to the normal copy of the gene on their second X chromosome.
In the tissues of certain carrier females, however, the cells that have silenced the X chromosome with a mutated gene cannot compensate for the defect in the cells that have silenced the X chromosome with the normal gene. Nathans and his team saw such a pattern when they examined the retinas of mice that were carriers for mutations in the Norrie disease gene, which is located on the X chromosome. The Norrie disease gene codes for a protein, Norrin, which controls blood vessel formation in the retina. Women who are carriers for Norrie disease can have defects in their retinas, but some women are more affected than others, and sometimes one eye is more affected than the other eye in the same individual.
The team found that in female mice that were Norrie disease carriers, variation in blood vessel structure corresponded to localized variations in X chromosome inactivation. When the X chromosome carrying the normal copy of the Norrie disease gene was silenced in a group of cells, the blood vessels nearby failed to form properly. In contrast, when the X chromosome carrying the mutated copy of the Norrie disease gene was silenced, the nearby blood vessels developed normally.
“X chromosome inactivation is a fascinating aspect of mammalian biology,” says Nathans. “This new technique for visualizing the pattern of X chromosome inactivation should be particularly useful for looking at the role that this process plays in brain development, including the ways that it contributes to differences between the left and right sides of the female brain, and to differences in brain structure between males and females and among different females, including identical twins.”
Gene linked to common intellectual disability
University of Adelaide researchers have taken a step forward in unravelling the causes of a commonly inherited intellectual disability, finding that a genetic mutation leads to a reduction in certain proteins in the brain.
ARX is among the top four types of intellectual disability linked to the X-chromosome in males. So far, 115 families, including many large Australian families, have been discovered to carry an ARX (Aristaless related homeobox) mutation that gives rise to intellectual disability.
"There is considerable variation in the disability across families, and within families with a single mutation. Symptoms among males always include intellectual disability, as well as a range of movement disorders of the hand, and in some cases severe seizures," says Associate Professor Cheryl Shoubridge, Head of Molecular Neurogenetics with the University of Adelaide’s Robinson Institute.
ARX mutations were first discovered by the University of Adelaide’s Professor Jozef Gecz in 2002. To date, researchers have detected 52 different ARX mutations and 10 distinct clinical syndromes.
Associate Professor Shoubridge is lead author of a new paper on ARX intellectual disability published in the journal Human Molecular Genetics.
In laboratory studies, Associate Professor Shoubridge’s team has shown that mutations lead to a significant reduction in ARX proteins in the brain, but the actual causes and mechanisms involved in this remain unknown. Her team tested six genes that the ARX protein interacts with, and found that one of them - a gene likely to be important to early brain development - appears to be adversely affected by the reduction of ARX proteins.
"This plays an important role in setting up architecture and networks in the brain, which become disrupted due to the mutation", Associate Professor Shoubridge says.
"The discovery of this genetic link is an important step forward but there is still much work to be done. We’re now looking further at the mechanism of the reduction in ARX protein and what that means for the brain at a functional level."
Associate Professor Shoubridge says up to 3% of the population is affected by some kind of intellectual disability, costing $14.7 billion each year in Australia alone.
"The personal cost to families is enormous, especially in the most severe cases. Being able to unravel why and how these disabilities occur is very important to us and to the many people whose lives are affected by these conditions," she says.
(Source: adelaide.edu.au)
Fragile X makes brain cells talk too much
The most common inherited form of mental retardation and autism, fragile X syndrome, turns some brain cells into chatterboxes, scientists at Washington University School of Medicine in St. Louis report.
The extra talk may make it harder for brain cells to identify and attend to important signals, potentially establishing an intriguing parallel at the cellular level to the attention problems seen in autism.
According to the researchers, understanding the effects of this altered signaling will be important to developing successful treatments for fragile X and autism.
“We don’t know precisely how information is encoded in the brain, but we presume that some signals are important and some are noise,” says senior author Vitaly Klyachko, PhD, assistant professor of cell biology and physiology. “Our theoretical model suggests that the changes we detected may make it much more difficult for brain cells to distinguish the important signals from the noise.”
The findings appear Feb. 20 in Neuron.
Fragile X is caused by mutations in a gene called Fmr1. This gene is found on the X chromosome, one of the two sex chromosomes. Females have two copies of that chromosome, while males only have one. As a result, males have fragile X syndrome more often than females, and the effects in males tend to be more severe.
Symptoms of fragile X include mental retardation, hyperactivity, epilepsy, impulsive behavior, and delays in the development of speech and walking. Fragile X also affects anatomy, leading to unusually large heads, flat feet, large body size and distinctive facial features. Thirty percent of fragile X patients are autistic.
Scientists deleted the Fmr1 gene many years ago in mice to create a model of fragile X. Without Fmr1, the mice have abnormalities in brain cells and social and behavioral deficits similar to those seen in human fragile X.
According to Klyachko, nearly all fragile X mouse studies in the past two decades have focused on how Fmr1 loss affects dendrites, the branches of nerve cells that receive signals. In contrast, his new study finds significant changes in axons, the branches of nerve cells that send signals.
Normally, signals travel down the axon as surges of electrical energy. These surges only last for tiny fractions of a second, briefly causing the axon to release compounds known as neurotransmitters into the short gap between nerve cells. The neurotransmitters cross the gap and bind to their receptors on the dendrite to convey the signal.
When Klyachko monitored electrical surges along axons in the fragile X mice, though, he discovered that they lasted significantly longer. This caused release of more of neurotransmitters from the axon. When it should have stopped talking, the axon continued to chatter.
“The axons are putting out much more neurotransmitter than they should, and we think this confuses the system and overloads the circuitry,” Klyachko explains. “It may also create problems in terms of brain cells using up their resources much more quickly than they normally would.”
Infusing synthetic copies of the gene’s protein, called FMRP, into brain cells from the mouse model rapidly restored the electrical surges to their normal length.
Additional experiments revealed that FMRP works by interacting with one of the biggest channels on the surfaces of axons. These channels let electrically charged potassium ions into the axons, helping to shape and control the duration of the electrical surge.
In healthy brain cells, the main function of these channels is to prevent the electrical surge from getting too long. With FMRP gone, the channel is active for a shorter time, prolonging the surge and overwhelming the dendrite with too much chatter.
Klyachko and his colleagues are now studying the connections between FMRP and the channel it interacts with in axons. They hope to learn more about how information is encoded and processed at the level of individual brain cells. These insights one day may help clinicians better diagnose and treat many kinds of mental disorders.