Scientists identify gene mutation in autism | Reuters

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Scientists identify gene mutation in autismSun Dec 17, 2006 6:05 PM GMT

PARIS (Reuters) - French scientists have identified genetic mutations in a small number of children with autism which could provide insight into the biological basis of the disorder.

They sequenced a gene called SHANK3 in more than 200 people with autism spectrum disorders (ASD), which includes autism, and found mutations in the gene in members of three families.

ASD covers a range of problems that affect communication, social interaction, verbal skills and behavior.

"These mutations concern only a small number of individuals, but they shed light on one gene ... that is involved in autism spectrum disorders," Bourgeron, of the Pasteur Institute in Paris, said in a report in the journal Nature Genetics.

ASD, which affect six out of 1,000 children, range from mild to severe forms. The disorders are caused by chromosomal rearrangements in 3 to 6 percent of cases.

In people with cognitive deficits and with autistic behavior a part of their chromosome 22 is often affected. That region contains the SHANK3 gene.

In all three families identified in the study, the researchers found they had various types of mutations in the gene. Two brothers in one family had small deletions, while another child in a different family had significant deletions.

A girl with a deletion of SHANK 3 in the third family suffered from autism while her brother, who had an additional copy of the gene, had a mild form of autism called Asperger syndrome.

The cause of autism is unknown. It usually develops before the age of 30 months. A minority of autistic children, who are known as autistic savants, show remarkable artistic, musical or mathematical skills.

The protein encoded by SHANK3 interacts with other proteins called neuroligins, which have a role in giving impulses to the brain, spinal column and nerves.

[Guest guest]

Note also that Shank protein forms signalling processes with calcium

channels... wonder if they will refer to that in their paper... or by

any chance mention how sensitive these mechanism are to environmental

influences...

J Neurosci. 2005 Feb 2;25(5):1037-49.

Association of CaV1.3 L-type calcium channels with Shank.

* Zhang H, Department of

Physiology, University of Texas Southwestern Medical Center at Dallas,

Dallas, Texas 75390, USA.

Neurons express multiple types of voltage-gated

calcium (Ca2+) channels. .... . We established that CaV1.3a and Shank

localized to postsynaptic locations in cultured rat hippocampal

neurons. By expressing epitope-tagged recombinant CaV1.3 subunits in

rat hippocampal neuronal cultures, we demonstrated that the presence of

Shank-binding motifs in CaV1.3a sequence is both necessary and

sufficient for synaptic clustering of CaV1.3 L-type Ca2+ channels.

..... , we demonstrated an importance of Shank-binding motif in

CaV1.3a sequence for phosphorylated cAMP response element-binding

protein (pCREB) signaling in cultured hippocampal neurons. Our results directly link CaV1.3 neuronal L-type Ca2+ channels to macromolecular signaling complex formed by Shank and

other modular adaptor proteins at postsynaptic density and provide

novel information about the role played by CaV1.3 L-type Ca2+ channels

in pCREB signaling.

PMID: 15689539 [PubMed - indexed for MEDLINE]

J Neurosci. 2003 Apr 15;23(8):3446-56.

Interactions with PDZ proteins are required for

L-type calcium channels to activate cAMP response element-binding

protein-dependent gene expression.

* Weick

JP, * Groth

RD, * Isaksen

AL, * Mermelstein PG.

Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.

After brief periods of heightened stimulation,

calcium entry through L-type calcium channels leads to activation of

the transcription factor cAMP response element-binding protein (CREB)

and CRE-dependent transcription. Many of the details surrounding the

mechanism by which L-type calcium channels are privileged in signaling

to CREB, to the exclusion of other calcium entry pathways, has remained

unclear. We hypothesized that the PDZ interaction sequence contained

within the last four amino acids of the calcium channel alpha1C

(Ca(V)1.2) subunit [Val-Ser-Asn-Leu (VSNL)] is critical for L-type

calcium channels (LTCs) to interact with the signaling machinery that

triggers activity-dependent gene expression. To disrupt this

interaction, hippocampal CA3-CA1 pyramidal neurons were transfected

with DNA encoding for enhanced green fluorescent protein tethered to

VSNL (EGFP-VSNL). EGFP-VSNL significantly attenuated L-type calcium

channel-induced CREB phosphorylation and CRE-dependent transcription,

although somatic calcium concentrations after stimulation remained

unchanged. The effect of EGFP-VSNL was specific to the actions of

L-type calcium channels, because CREB signaling after NMDA receptor

stimulation remained intact. The importance of the PDZ interaction

sequence was verified using dihydropyridine (DHP)-insensitive alpha1C

subunits. Neurons transfected with alpha1C lacking the terminal five

amino acids (DHP-LTCnoPDZ) exhibited attenuated CREB responses in

comparison with cells expressing the full-length subunit (DHP-LTC). Collectively,

these data suggest that localized calcium responses, regulated by

interactions with PDZ domain proteins, are necessary for L-type calcium

channels to effectively activate CREB and CRE-mediated gene expression.

PMID: 12716953 [PubMed - indexed for MEDLINE]

Natasa

>> _Click here: Scientists identify gene mutation in autism | Science & Health | > Reuters.co.uk_ >

(http://today.reuters.co.uk/news/articlenews.aspx?type=healthNews & storyID=2006-12-17T180540Z_01_L17519993_RTRIDST_0_HEALTH-FRANCE-AUTISM-DC.X> ML & WTmodLoc=SciHealth-C1-Headline-9) > > Scientists identify gene mutation in autism> Sun Dec 17, 2006 6:05 PM GMT> > PARIS (Reuters) - French scientists have identified genetic mutations in a > small number of children with autism which could provide insight into the > biological basis of the disorder. > They sequenced a gene called SHANK3 in more than 200 people with autism > spectrum disorders (ASD), which includes autism, and found mutations in the gene > in members of three families. > ASD covers a range of problems that affect communication, social interaction, > verbal skills and behavior. > "These mutations concern only a small number of individuals, but they shed > light on one gene ... that is involved in autism spectrum disorders," > Bourgeron, of the Pasteur Institute in Paris, said in a report in the journal > Nature Genetics. > ASD, which affect six out of 1,000 children, range from mild to severe forms. > The disorders are caused by chromosomal rearrangements in 3 to 6 percent of > cases. > In people with cognitive deficits and with autistic behavior a part of their > chromosome 22 is often affected. That region contains the SHANK3 gene. > In all three families identified in the study, the researchers found they had > various types of mutations in the gene. Two brothers in one family had small > deletions, while another child in a different family had significant > deletions. > A girl with a deletion of SHANK 3 in the third family suffered from autism > while her brother, who had an additional copy of the gene, had a mild form of > autism called Asperger syndrome. > The cause of autism is unknown. It usually develops before the age of 30 > months. A minority of autistic children, who are known as autistic savants, show > remarkable artistic, musical or mathematical skills. > The protein encoded by SHANK3 interacts with other proteins called > neuroligins, which have a role in giving impulses to the brain, spinal column and > nerves.>