Archive for the ‘Autism Genetics’ Category
Vasoactive intestinal peptide is a peptide hormone produced in the gut, the pancreas, and the brain. It has a number of different effects on the body:
- With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen. Its role in the intestine is to greatly stimulate secretion of water and electrolytes, as well as dilating intestinal smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility.
- It also has the function of stimulating pepsinogen secretion by chief cells.
- It is also found in the brain and some autonomic nerves. One region of the brain includes a specific area of the suprachiasmatic nuclei (SCN), the location of the ‘master circadian pacemaker‘. The SCN coordinates daily timekeeping in the bodyand VIP plays a key role in communication between individual brain cells within this region. Further, VIP is also involved in synchronising the timing of SCN function with the environmental light-dark cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian circadian timekeeping machinery.
- VIP helps to regulate prolactin secretion. [Prolactin inhibits the sex drive]
- It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilationas well as having a positive inotropic and chronotropic effect. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP Wiki
Vasoactive intestinal peptide has been connected to autism. This is from a 2001 news report:
A new discovery by Nelson, Grether, and colleagues, however, may bring investigators even closer to the origins of autism than the cerebellum has.
They collected blood that had been taken from 246 subjects at birth and stored in a deep freezer. Of the 246 subjects, 69 had autism, 60 mental retardation, 63 cerebral palsy, and 54 were healthy controls. They then analyzed the blood samples for five different brain proteins—nerve growth factor, substance P, brain-derived neurotrophic factor, calcitonin gene–related peptide, and vasoactive intestinal peptide.
They found comparable amounts of nerve growth factor and substance P in blood samples from all four groups of subjects. However, they found much higher levels of the other three proteins in blood taken from subjects with autism and with mental retardation than in blood taken from the cerebral palsy subjects and healthy controls. And what was especially intriguing is that while about a quarter of the autism subjects did not develop symptoms of autism until they were at least 1 year old, they already had large amounts of these three proteins at birth.
Thus the three proteins may well play causative roles in autism, Nelson and her team concluded, and they believe their findings also suggest that autism is already present at birth or maybe even before. Some other evidence, in fact, also implies that this is the case, she pointed out.
For instance, if mouse-embryo brains are exposed to vasoactive intestinal peptide, they flourish; but if the brains are deprived of this protein, they do not grow properly. Vasoactive intestinal peptide is also known to be involved in the sleep-wake cycle, and autism patients often have sleep problems. Vasoactive intestinal peptide is also known to be made in the gut, and autism patients often have gastrointestinal problems. Small Steps Mark Progress in Understanding Autism
Symptoms of too much vasoactive intestinal peptide are likely to correlate with symptoms of VIPoma, which produces too much vasoactive intestinal peptide:
The major clinical features are prolonged watery diarrhea [..] and symptoms of hypokalemia and dehydration. […] Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hyperkalemia and impaired glucose tolerance occur in < 50% of patients. During attacks of diarrhea, flushing similar to the carcinoid syndrome occur rarely. VIPoma Wiki
Okay, hands up if you have autism and also have gastrointestinal problems, sleep problems, a dampened sex drive, acid reflux, and impaired glucose tolerance? If so, Occam’s razor suggests vasoactive intestinal peptide might be involved.
We investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene as a candidate gene for autism. We searched for mutations in the VIPR2 gene in autistic individuals, and 10 novel polymorphisms were identified. Three polymorphisms in the upstream region were studied in detail, and there was no significant difference in the frequencies between the autistic group (n = 14) and unrelated controls (n = 52). The distribution of the genotypes in two of the three polymorphisms differed somewhat between autistic subjects with gastrointestinal problems and those without. Moreover, there was a trend showing a correlation between the genotypes for the third polymorphism and the severity of stereotypical behavior as ranked by the Gilliam Autism Rating Scale. These preliminary results suggest that VIPR2 may have a role in gastrointestinal symptoms and stereotypical behaviors in autism, although a larger collection of samples suitable for transmission disequilibrium tests is necessary to validate the results. A Study of Novel Polymorphisms in the Upstream Region of Vasoactive Intestinal Peptide Receptor Type 2 Gene in Autism
The symptoms are so similar to some people’s experience of food chemicals – particularly salicylates, that I suspect salicylates may work to aggravate underlying VIPR2 polymorphisms somehow.
An excellent overview of autism genetics:
Identical twin studies put autism’s heritability in a range between 0.36 and 0.957, with concordance for a broader phenotype usually found at the higher end of the range. Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population. To What Extent Do Genes Cause Autism?
These are the genes that the article runs through:
SERT – rigid compulsive behaviours, social adversity, depression as a result of social adversity, hyperserotonemia.
GABA – GABRA4 through interaction with GABRB1. GABRB3 – savant skills. [Interestingly GABRA1 is associated with Juvenile Myoclonic Epilepsy – the individual I know with JME scores very high-normal on an AQ test.]
Engrailed 2 (EN2) – cerebellar development.
3q25-27 region – autism and asperger’s, function unknown.
7q21-q36 region, REELIN (RELN) – memory formation, neurotransmission, synaptic plasticity.
SLC25A12 – AGC1, mitochondrial aspartate/glutamate carrier.
HOXA1 and HOXB1 – brain stem development. Possibly head circumference. May interact with teratogens like valproic acid. Undermethylation?
PRKCB1 – Protein kinase C beta 1, diverse signalling pathways. Involvement in arachidonic acid cascade?
FOXP2 – Developmental language and speech deficits.
UBE3A – Angelman syndrome, Rett syndrome. Development delay, hand flapping, happy demeanour.
Shank3/ProSAP2, 22q13 and Neuroligins – neuroligins regulate structural organisation of neurotransmitter receptors. SHANK3 – encodes a synaptic scaffolding protein. Interaction between SHANK3 and 22q13 – global development delay, delayed speech, delayed cognitive abilities, high pain tolerance, chewing and mouthing. Neuroligin-3 – poor social skills and increased intelligence.
MET (MET receptor tyrosine kinase) – brain development, regulation of the immune system, repair of GI system. Disrupted neuronal growth in cerebral cortex, smaller cerebellum. MET variants influence cancer metastases – cancer less likely in these autistic children.
Neurexin 1 – CNTNAP2 – communication between nerve cells, regulating chemical transmission, early brain development.
GSTP1 – glutathione s-transferase acting in mother during pregnancy increasing risk of autism in child.
Other candidate loci include the 17q21 region, the 3p24-26 locus, PTEN and 15q11-q13.
Other possibles: SLC6A2 (Social phobia), FMR1 (Fragile-X), 5-HT-1Dbeta (OCD), 7q11.23 (William’s syndrome, language impairment), 4q34-35, 5q35.2-35.3, 17q25 (Tourette syndrome), 2q24.1-31.1 (Intelligence), 6p25.3-22.3 (Verbal IQ), 22q11.2 (Visio-Spatial IQ).
The genes mentioned above aren’t the only genes with suspected involvement in autism – there are methylation genes too:
The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism
And a number of studies linking low functioning MAO with increased severity.
These comments are from the biggest autism twin study mentioned in the article:
High heritability was found for extreme autistic-like traits (0.64-0.92 for various cutoffs) and autistic-like traits as measured on a continuum (0.78-0.81), with no significant shared environmental influences. All three subscales were highly heritable but showed low covariation. In the genetic modeling, distinct genetic influences were identified for the three components. Genetic heterogeneity between the three components of the autism spectrum: a twin study
As you can see there are a huge number of different genes implicated in the etiology of autism. I’ve often thought of the label ‘autism’ as being a bit like a rubbish bin diagnosis into which many different types of people are put because they fit a few basic criteria. In the past those people would have been put into different criteria – for example they would have been defined as ‘retarded’ or ‘psychotic’ or ‘shy’. Some autistics are mentally retarded, some have increased intelligence. Some have savant skills. Some rock and flap and poo smear. Others write computer programs, design jet planes, or teach astrophysics for a living. Some don’t talk at all. Others never stop talking. I identify closely with some of the autistics whose blogs I read (I find myself thinking she’s got exactly the same symptoms/personality as me right the way down to the fear of having to use a telephone). I think other autistics whose blogs I read are just plain weird (I find myself thinking he’s one of those mad/paranoid/illogical/retarded autistics). It takes many different genes to produce many different aspects of the personality.
Following on from the two genetic theories of autism I’ve discussed before, and the questioning of the odds involved in new mutations causing autism, here’s a little more news that slipped under the radar recently.
There is a new wrinkle to the genetic research however. Based on family studies, scientists have long characterized autism-linked genes as “heritable.” But recent research shows a surprisingly large number of mutations tied to autism are “de novo” glitches that arise spontaneously in children whose parents don’t carry them.
Such spontaneous mutations have come to light by studying so-called “structural changes” in the genome, which, if DNA’s chemical letters were arranged in book form, would consist of largish mistakes such as duplicated and missing pages. A recent study that got much less attention than the Poling story showed that 7% of kids with autism carry structural changes not found in their parents, compared with less than 1% of such glitches seen in the general population.
“This is really exciting, and a lot of people haven’t picked up on it yet,” says geneticist Stephen Scherer, a co-author of the study at the Hospital for Sick Children in Toronto.
It’s likely that many more such changes will be linked to ASDs as researchers examine a wider array of cases with new gene-scanning tools. Some researchers even theorize that the majority of autism cases stem from such spontaneous mutations.
Why would genes linked to autism be so mutation-prone?
Consider a mutation on chromosome 16 recently tied to autism. The glitch is in a DNA region containing so-called “morpheus” genes, which changed very rapidly as evolution produced ever brainier apes. The genes may well help shape cognitive capacities specific to apes and humans, including ones affected by autism.
Since fast mutation goes hand in hand with fast evolution, it’s likely that the new autism-linked gene lies in a DNA “hotspot” prone to spontaneous mutation. In short, the same phenomenon that helped to rapidly evolve our braininess may contribute to autism. Tracing autism’s roots
So first off – the ‘surprisingly large number’ of de-novo mutations in autistic children has now fallen from ten percent to seven percent (7%) of autistics versus 1% of the general population. The vast majority of autistics aren’t involved in this process.
And second – try as I might, I can’t find any evidence that mutations in Morpheus genes are affected by DNA methylation, transposons, or anything else. This seems to be an effect entirely independent of dietary folate and blah blah blah during pregnancy. In fact, it appears to be an inbuilt evolutionary mechanism for increasing brain power.
It seems that in this case the far-out New Age beliefs that autistics are ‘crystal children’ who are ‘the next stage in our evolution’ are less far-off the mark than WAPF member’s judgemental beliefs that autistics are ‘Pottenger’s children’ whose DNA has been ‘damaged’ by their parents diets.
About 30% of autistics have elevated serotonin levels, and autism has been linked to polymorphisms in SERT – a serotonin transporter. Chris sent me this great link the other day:
Many children with autism have elevated blood levels of serotonin – a chemical with strong links to mood and anxiety. But what relevance this “hyperserotonemia” has for autism has remained a mystery.
New research by Vanderbilt University Medical Center investigators provides a physical basis for this phenomenon, which may have profound implications for the origin of some autism-associated deficits.
In an advance online publication in the Journal of Clinical Investigation, Ana Carneiro, Ph.D., and colleagues report that a well-known protein found in blood platelets, integrin beta3, physically associates with and regulates the serotonin transporter (SERT), a protein that controls serotonin availability.
Autism, a prevalent childhood disorder, involves deficits in language, social communication and prominent rigid-compulsive traits. Serotonin has long been suspected to play a role in autism since elevated blood serotonin and genetic variations in the SERT have been linked to autism. Sticky blood protein yields clues to autism
I love the way the science reporter thinks the link between elevated serotonin and autism is a mystery. He doesn’t know that serotonin has a powerful influence on shyness versus sociability.
The relationship of SERT with integrin beta3 is a good demonstration of how the same effects (in this case high serotonin) can be caused by several different genes.
Wait – wait… nope… still nothing to do with mercury.
This is another one for the ‘autism is all about glutamate’ file.
Fragile X syndrome is an X-linked syndrome with physical characteristics, mental retardation and autism.
Boys with the syndrome may have large testicles (macroorchidism), prognathism, hypotonia and autism, and a characteristic but variable face with large ears, long face, high-arched palate, gynecomastia, and malocclusion. Additional abnormalities may include lordosis, heart defect, pectus excavatum, flat feet, shortening of the tubular bones of the hands, and joint laxity. Females who have one fragile chromosome and one normal X chromosome may range from normal to mild manifestations of the fragile X syndrome.
The genetics of Fragile X are quite straightforward:
The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disease itself is about 1 in every 4000 females.)
Normally, the (FMR1 gene contains between 6 and 55 repeats of the CGG codontrinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.
Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears ‘fragile’ under the microscope at that point, a phenomenon that gave the syndrome its name.
Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. Fragile X Wiki
Today Grey Matter/White Matter linked to a press release reporting new progress in fragile X research.
ATLANTA, March 10 (UPI) — A U.S. team of scientists has identified several drugs and small molecules that reverse features of fragile X syndrome — a form of mental retardation.
The scientists, led by Stephen Warren of Emory University, made their discoveries using a new drug screening method in Drosophila (fruit flies), setting the stage for development of new treatments for the syndrome, one of the leading known causes of autism.
Warren led a group of scientists that discovered in 1991 that the FMR1 gene is responsible for fragile X syndrome.
In the current experiment, scientists discovered when FMR1-deficient fly embryos were fed food containing increased levels of glutamate, they died during development.
The scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. In addition, each well contained one compound from a library of 2,000 drugs and small molecules. Using that screening method, the scientists uncovered nine molecules that reversed the lethal effects of glutamate.
The study that included Shuang Chang, Steven Bray and Peng Jin of Emory, Zigang Li of the University of Chicago and Daniela Zarnescu from the University of Arizona appears online in the journal Nature Chemical Biology. Progress reported in fragile X research
In a longer news article we find:
A variety of scientific evidence suggests that increasing glutamate neuronal transmission may be beneficial in autism and in fragile X syndrome. Imaging studies demonstrate that areas of the brain that are extremely rich in glutamate transmission are less active in autistic patients. Molecular studies suggest that although genes involved in the AMPA-type glutamate receptor are more active in autistic patients, the density of AMPA-type glutamate receptors is decreased. Drugs that reduce glutamatergic transmission induce symptoms similar to those seen in autistic patients. Taken together, these facts suggest that enhancing AMPA receptor activity may be beneficial in autistic patients. New Drug That Enhances Glutamate Transmission In The Brain Being Evaluated For Fragile X
Wikipedia also mentions:
One hypothesis is that many symptoms are caused by unchecked activation of mGluR5, a metabotropic glutamate receptor, which was found in a 2007 study to contribute significantly to the pathogenesis of the disease; this suggests that mGluR5 blockers could be used to treat fragile X syndrome.
I do not have fragile X syndrome. But dietary free glutamate makes me very withdrawn and inhibited and later incredibly sleepy, so there is clearly something going on with the way I process and use glutamate. Glutamate is also implicated in autism through the gene for neurexin 1.
Wake up folks! It’s still not mercury.
The “new mutations” genetic theory of autism is one pioneered by scientists such as Professors Michael Wigler and Jonathan Sebat at the Cold Spring Harbor Laboratory on Long Island, New York. This short piece from the New Scientist explains their theory:
Duplications or deletions of portions of the genome may cause many – if not most – cases of autism.
Such errors can alter the number of copies of particular genes in the regions affected. These copy-number variations are 10 times as common in autistic children as in other children.
A team led by Jonathan Sebat of Cold Spring Harbor Laboratory on Long Island, New York, examined 118 families that have one autistic child and 99 families with children who are not autistic. Ten per cent of the autistic children, but only 1 per cent of the other children, had copy-number variants in their genomes that didn’t appear in their parents (Science, DOI: 10.1126/science.1138659).
The copy-number variants tend to affect different genes in each autistic child. This suggests that autism is not caused by a single genetic defect. Clues to autism revealed in copied genes
I’ve spent most of my time recently talking about single nucleotide polymorphisms – where one letter of a gene is substituted for another letter. Here, the scientists studied deletions and duplications of genes. Deletions and duplications and variants of genes are normal, very common, and widely found in the genetic code of all human beings. What the scientists have found here is that new deletions and duplications are present in a small but significant minority of autistic children – ten percent of autistic children to be exact, whereas they are normally present in about one percent of births. This is not at all surprising, considering the correlation of low-functioning DNA methylation genes with autism.
What we have to be cautious about is concluding causation from this – deletions/duplications rarely cause any observable changes in people, and they can occur anywhere in our genome – which consists of tens of thousands of different genes. For deletions/duplications to actually have some effect on the likelihood of being born with autism, they need to occur in genes that affect personality or the brain and nervous system.
What does the rest of the scientific community think?
Much of the autism research community believes there may be roughly six major genes involved in autism, and maybe 30 others that may confer some risk. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism. Largest Ever Autism Study Identifies Two Genetic Culprits
Even if we included all of the personality and nervous system genes, that’s still a pretty narrow selection of genes that would have to be deleted or duplicated in order to produce changes in the child’s personality, let alone changes that cause autism.
One of the regular genes identified in autism by the Autism Genome Project is CNTNAP2. CNTNAP2 encodes neurexins – synaptic cell surface proteins – which are involved in glutamate functioning in the nervous system and brain. According to Entrez Gene, “This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome.” That’s a lot of room for variation isn’t it?
Wow. Donna Williams’ family history sounds just like mine!
I was born into a very challenged and challenging household of unusual, eccentric, personalities. Various combinations of mood, anxiety, compulsive disorders, addiction, rage, dyslexia, ADHD, Asperger’s, autism, suicide, Crohn’s, Colitis, Coeliac, Diabetes, eczema, asthma, croup, hives and allergy rashes all run in various side of my family, going back generations on my father’s side.
Not all people with autism have my physical, sensory-perceptual, language processing, neurological integration or co-morbid mood, anxiety or compulsive disorders. Most of these issues run on one or both sides of my family. I feel that what I inherited was the combined impact of the challenges of both my parent’s sides of the family and that under certain environmental conditions, these things expressed themselves in early infancy, causing the developmental breakdown that presented as a ‘psychotic infant’, disturbed child, autistic adult. Autism; it ain’t all physical
I was going to say I can’t think of a case of suicide – but I can – my dad’s cousin was a millionaire who lived in a stately hall in Bakewell, and he killed himself.
No Crohn’s/colitis/coeliac as far as I know – just plenty of garden-variety IBS. Also some kidney stones and gallstones.
Like me, Williams seems to have inherited most of her autie personality from her father. My father is a boffin, crazy inventor, tinkerer, collector, and all-round know-it-all.
I even have something in my family history that Williams doesn’t – my maternal grandfather’s sister had intractable epilepsy and was locked up in a sanitarium until she died.
I would have loved to have met my great grandfather Beau Pré. He was an African missionary – a very angry man by most accounts – an alcoholic, who died in the African jungle of an asthma attack.
I am so repeating myself here. Do you think if I keep saying “IT’S GENETIC” some of the chelators and the gut bacteria folks and the vitamin deficiency zealots will eventually stop and listen?
Or am I talking to a brick wall here?