Use this chromosome map to explore genes associated with autism.
Although twin studies suggest that autism is highly heritable, no one gene has been unambiguously identified as a cause of the disorder. The search for candidate genes for autism is complicated by the fact that the majority of genes associated with the disorder are associated with only one specific symptom. This finding holds important implications for diagnosis and treatment. If it is the case that specific genes contribute to specific symptoms – such as social difficulties, communication deficits, or repetitive behaviors – it may be useful to study these symptoms separately rather than adopt a broad approach. This finding is also consistent with the view that the underlying causes of autism are highly complex and the likely result of interactions between a multitude of genes. Most genes known to play a role in brain development are potential candidates for conferring susceptibility to autism.
EN2 (Engrailed homeobox 2) is a homeobox gene that is critical to the development of the midbrain and cerebellum. Like other homeobox genes, it regulates morphogenesis – the combined process of combined processes of cell division, differentiation, and organ development.
EN2 is a human homolog of the engrailed gene, which is found in Drosophila. En2 mouse mutants have anatomic phenotypes in the cerebellum that resemble cerebellar abnormalities reported in autistic individuals. Four candidate genes studies have explored the relationship between EN2 and autism – three found a positive association.
Reelin is a protein found mainly in the brain. It plays an important role in brain development, and is a regulator of early neuronal migration and positioning. In adults, reelin is important to the processes of learning and memory, and is critical to inducing and maintaining long-term potentiation. It modulates the synaptic plasticity by enhancing LTP induction and maintenance. Mice that lack the reelin gene (also known as RELN) tend to acquire unbalanced jerky movements, where they appear to be reeling – hence the name reelin. Three candidate gene studies support an association between autism and reelin, four do not. Reelin is also associated with a number of other cognitive disorders, including schizophrenia and Alzheimer’s disease.
GABA-A RECEPTOR, BETA-3 POLYPEPTIDE (GABRB3) maps to chromosomal region 15q11.2-q12 in humans. GABA is the main inhibitory neurotransmitter in the adult brain. During neurotransmission GABA activates the GABA-A receptor on the postsynaptic neuron. When this happens, the GABA-A receptor changes shape – thereby opening a pore in the postsynaptic dendrite. This allows chloride ions, which carry an electric charge, to enter the dendrite. As a result, the charge in postsynaptic dendrite becomes more negative, which makes it more difficult to generate an action potential. This is one of the fundamental processes of learning. Because abnormalities in the levels of GABA have been found in individuals with autism, it is logical to examine whether polymorphisms in GABA receptor genes can contribute to the disorder. GABRA3 has become a candidate gene for autism, but findings have been somewhat mixed.
Depression: The serotonin transporter gene, known as either 6-HTT or SLC6A4, appears to be a principal site of action of many tricyclic antidepressants, such as amoxapine and impramine, and may mediate behavioral responses to cocaine and amphetamines. Ogilvie and colleagues (1996) identified 3 novel alleles of the variable number tandem repeat (VNTR) region. They found that unipolar depression and major depressive disorder patients were significantly more likely to carry an excess of an allele with 9 copies of the VNTR element.
Autism: Autistic individuals consistently show elevated platelet serotonin levels, and have been shown to respond to serotonin reuptake inhibitor (SRI) medications. This has led researchers to examine the role of genes involved in serotonin regulation as potential causes of autism. Results have been mixed,
The argine-vasopressin (AVP) hormone system has been shown to affect social behavior. Because it mediates the influence of AVP, the AVP receptor 1a (AVPR1a) is a candidate gene for autism. Although it remains a prominent candidate gene for the disorder, evidence from two association studies have found only a weak positive association.
Matsuura et al. (1997) identified 4 truncating mutations in the UBE3A gene in patients with Angelman Syndrome (AS). AS is characterized by impaired motor and cognitive development, sleep disturbance, clumsy gait, seizures and irregular behaviors such as flapping and bursts of laughter. In mice, these features correlate with the loss of maternal-specific expression of Ube3a in the hippocampus and cerebellum. UBE3A has also been explored a possible candidate gene for autism and is supported by Nurni and colleagues (2001), but not by Veenstra-VanderWeele et al. (1999).
Lai and colleagues (2001) identified FOXP2 as a causal gene for a severe speech and language disorder in a three-generation pedigree. Because language impairments are a hallmark of autism, the gene has been examined as a potential cause of the disorder. Results from two independent family studies, however, failed to find an association between FOXP2 and autism.