[autismo-biologia] Rare structural variation of synapse and neurotransmission genes in autism

[daniela marianicerati]

Segnalo l’articolo
 
Rare structural variation of synapse and neurotransmission genes in autism
X Gai1, H M Xie1, J C Perin1, N Takahashi2, K Murphy1, A S Wenocur1, M D'arcy1, 
R J O'Hara1, E Goldmuntz3,6, D E Grice4, T H Shaikh5, H Hakonarson6,7,8, J 
D Buxbaum2, J Elia9,10 and P S White1,6,11
Molecular Psychiatryadvance online publication 1 March 2011; doi: 
10.1038/mp.2011.10
 
L’articolo puo’ essere letto integralmente al link
http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201110a.html
 
Gli autori hanno studiato le CNVs  (genome copy-number variations) in campioni 
numericamente consistenti di persone con autismo e in campioni di controllo. 

Numericamente le CNV sono frequenti sia nei probandi che nei controlli. Gli 
autori si sono quindi focalizzati sulle CNV presenti solo nelle persone con 
autismo per risalire dai geni alla funzione da essi codificata.
Questo tipo di ricerca ha condotto alla funzione sinaptica e alla 
neurotrasmissione. 

Copio alcuni stralci
“In this study we show that biological processes associated with synapse 
function and neurotransmission are significantly enriched, with replication, in 
ASD subjects versus controls”
 
Gli autori hanno poi studiato dei modelli animali portatori di anomalie dei geni 
contenuti nelle CNV trovando conferma di una correlazione tra genotipo e 
fenotipo similautistico(abnormal (±CNS) synaptic transmission, abnormal motor 
capabilities/coordination/movement, abnormal motor coordination/balance, reduced 
NMDA-mediated synaptic currents, abnormal impulse conducting system conduction, 
decreased startle reflex, abnormal miniature excitatory postsynaptic currentsand 
abnormal spatial learning)
 
“Analysis of phenotypes observed for mouse models of copy-variant genes 
established significant and replicated enrichment of observable phenotypes 
consistent with ASD behaviors”
 
Gli autori pertanto concludono
 
“These results implicate several new variants that involve synaptic function and 
glutamatergic signaling processes as important contributors of ASD 
pathophysiology”
 
Entrando più nel particolare copio altri stralci
 
“A total of 395 inherited CNVs (135 duplications, 256 heterozygous deletions and 
4 hemizygous deletions of the X chromosome) were identified in 286 autism 
subjects that were not present in healthy controls
 
Many of these processes were associated with synaptic function and 
neurotransmission, including cell–cell signaling (P=1.97 × 10−7), transmission 
of nerve impulse (P=7.06 × 10−5), synaptic transmission (P=8.05 × 10−5), neuron 
adhesion (P=2.06 × 10−3), central nervous system development (P=4.30 × 10−3), 
regulation of neurotransmitter levels (P=4.88 × 10−3), neurotransmitter 
secretion (P=1.30 × 10−2) and neurotransmitter transport (P=2.95 × 10−2).
Autism CNV genes frequently associated with terms related to synapse function 
and neurotransmission included previous candidates CNTN4, NRXN1 and PARK2, as 
well as genes CNTN6, CTNND2, GRIN2A, NCAM2, GRM7, GRM8 and RCAN1.
Le conclusioni degli autori sono le seguenti
 
“our results do consistently and independently implicate possible pathways, 
functions and gene sets that can be readily investigated by follow-up genomic 
and experimental investigation.
Our current results extend these findings and, more importantly, for the first 
time provide statistical evidence that synaptic function and glutamate-mediated 
neurotransmission are contributing factors in autism etiology”
Lo spostamento dai geni alle sinapsi e alla neurotrasmissione dovrebbe stimolare 
la ricerca di target per nuovi farmaci. 

Sappiamo che dall’ipotesi alla commercializzazione di un farmaco la strada è 
lunga, ma, come dice Gianni Rodari “Chi non parte in verità in nessun posto 
arriverà”