Clinical findings in autism and relevance
of dysfunctional calcium signalling in:
new ** HIV
of abnormal biomedical findings in autism
There are presently two identified genetically inherited disorders
of mutations in calcium channels with high incidence of autism.
Timothy syndrome is caused by mutations in
CACNA1C, the gene encoding Ca(V)1.2 calcium channel, causing
loss of channel inactivation and suspected intracellular calcium
overload. This dysfunction causes a multisystem disorder including
congenital heart disease, webbing of fingers and toes, immune
deficiency, intermittent hypoglycemia and cognitive abnormalities.
Frequent seizures, irregular sleep patterns, dysmorphic facial
features, myopia, motor abnormalities and small and decaying
teeth have also been recorded in affected individuals .
The exact incidence of autism is unknown but could be as high
as 80 percent.
A mutation in a calcium channel gene CACNA1F,
encoding for Cav1.4 L-type calcium channel, that results in
retinal disorder and visual impairments has been observed in
a New Zealand familiy. Although female members of the family
display visual impairments, the symptoms are more severe in
male family members. Five of the affected males exibit intellectual
disability, with autism being present in three of those five
(see Motor/Sensory and Gender).
A study looking at mutations in genes encoding for calcium channels
in a broader sample of 461 individuals with autism found that
6 of them expressed a CACNA1H mutation, relating to Cav3.2 T-type
calcium channel. Although it was clear that the identified mutation
was not solely responsible for the condition, as some of the
nonaffected familiy members were found to carry the same mutation,
it was suggested that it could contribute to the development
of the ASD phenotype or influence its expression .
CACNA1H chromosomal location 16p13.3 is shared with with tuberous
sclerosis 2 gene (see below).
Similarly, a mutation in the gene encoding for Shank3,
a scaffolding protein that forms signalling complexes with at
least two of the voltage gated calcium channels, was recently
identified on chromosome 22q13 in a small number of affected
individuals [avaiting publication]. Shank proteins are involved
in calcium-mediated activation of gene transcription factor
CREB. (see Brain).
The haploinsufficiency of Shank3 is thought to be the responsible
for the neurological deficits of 22q13 Deletion Syndrome, in
which an estimated 50 percent of affected individuals exibit
autism-like symptoms .
Of note in this context that chromosome 22q13 has been identified
as one of the preferred location for integration
of human herpesvirus 6 DNA 
Calmodulin is another cellular protein that
binds to LTCC in neurons and other excitable cells and plays
an important role in regulating their activities and signalling
in CREB activation pathway [11598293,
Caldmodulin binds to tuberin, and its binding site is altered
by mutations linked to tuberous sclerosis [11811958,
Tuberin is encoded by tuberous sclerosis 2 gene, located on
chromosome 16p13.3 (see above). Mutations in
tuberous sclerosis genes 1 and 2 lead to a
rare genetic disorder characterized by seizures, mental retardation,
skin lesions and impaired functioning of many organs, including
brain, kidneys, heart, eyes and lungs. About half of affected
individuals have learning difficulties and a reported 16% meet
the diagnostic criteria for autism .
22q11.2 Deletion syndrome
(DiGeorge/velocardiofacial syndrome) is characterized by congenital
cardiovascular disease, dysfunction of parathyroid gland, immunodeficiency,
neurodevelopmental and psychiatric disorders. Autism spectrum
disorders as well as related Attention Deficit Hyperactivity
Disorder and sometimes Obsessive Compulsive Disorder are common
in children with the syndrome .
Affected children show hypoparathyroidism and abnormal calcium
homeostasis and, because of depressed cell-mediated immunity,
serious bacterial, viral and fungal infections [6973633,
Behavioral manifestations of this syndrome has been hypothesised
to result in part from haploinsufficiency of the catechol-O-methyltransferase
(COMT) gene, located within the 22q11 region .
Individuals with Cowden Syndrome, caused by
mutations in PTEN tumour suppressor gene, sometimes
exibit neurobehavioural symptoms similar to autism. Germline
mutations in the gene have been identified in a small subset
of individuals with non-syndromatic autism, as well as some
non-affected family members [15805158,
It has been suggested that inactivation of PTEN leads to behavioral
abnormalities seen in this disorder. It is of interest that
inactivation of PTEN has been observed to result in enhancement
of LTCC current in cardiac tissue .
Autism often co-occurs with phenylketonuria
(PKU), a genetic disorder in which the body lacks phenylalanine
hydroxylase, the enzyme necessary to metabolize phenylalanine
to tyrosine. A recent study has found that amongst the genes
upregulated by phenylalanine, and thus likely to be affected
in PKU disease, were L-type calcium channels, calcium/calmodulin-dependent
protein kinase (CaMK II), several genes related to transmitter
release, some glutamate receptor subunits and glutamate transporters
(also see Membrane for
Several polymorphisms in the genes encoding
proteins whose activity is directly modulated by calcium have
been suggeste to play a possible role to autism .
Although no firm genetic linkage has been established, it has
also been hypothesised that mutations in genes encoding sodium
channels SCN1A and SCN2A, and those encoding potassium channels,
such as CASPR2, may play a role [12610651,
On the other hand, physical disruption in the gene KCNMA1 encoding
BKCa channels and decreased activity of these channels in autism
have been observed recently .
Recent findings have pointed to functional coupling of BKCa
and LTCC channels on plasma membrane, and in additon excessive
calcium levels as result from either extracellular space or
intracellular store-released, are known to modulate functioning
of potassium channels [15141163,
(see also Epilepsy). It may be worth noting
that KCNMA1 gene location on chromosome 10q22 has been implicated
in preeclampsia 
and also that this chromosomal location has been identified
as a preferred integration site for hepatitis B virus .
Equally important are the findings of increased frequency of
polymorphisms in the genes related to the immune system
in autism, possibly indicating weakened defenses against and
elimination of pathogens such as viruses and bacteria from the
body, leaving a developing nervous system especially vulnerable
to direct and indirect pathogenic influences (see Immune
and Viruses). In addition
to several mutations in genes belonging to major histocompatibility
complex (MHC) region, related to immune function, being associated
with autism, the involvement of CREB-mediated events in regulation
and expression of these genes should be also be of interest
(see above, also see Brain).
One very interesting finding in recent times was the association
of genetic polymorphisms related to macrophage migration inhibitory
factor (MIF) in individuals with autism .
MIF is central in host immune reactions/viral clearance and
inflammatory responses. MIF favours viral neuroinvasion by compromising
the integrity of the blood-brain barrier (see Infectious
Agents re viral/bacterial aetiology in autism). It is very
closely linked to MCP-1 (elevated manifold in autism) and other
proinflammatory chemokines/cytokines, and its levels are inversely
related to regulatory cytokine IL-10 (low in autism). MIF also
plays a central part in gastrointestinal inflammation (see Gastrointestinal),
as well as cellular oxidative stress pathways - cysteine mediated
redox mechanisms (impaired in autism, see Oxidative
Stress). It is also appears to be directly involved in neuronal
function via at least one pathway, that of Angiotensin II. Levels
of MIF are often suppressed in fever. The expression levels
of MIF gene are partly regulated by calcium-dependent CREB.
autism has been link to some genetic mutations and polymorphisms
that raise suceptibility to oxidative stress (see Oxidative_Stress).
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