Table 1.

Emerging autism genes and available evidence for cerebellar pathology

GENE SYMBOL	GENE NAME	GENE FUNCTION	Cerebellar Pathologyb	Selected Human References	Selected Mouse References
Mendelian Disorders (Syndrome)
AHI1 (Joubert syndrome)	Abelson helper integration site 1	Encodes Jouberin, which interacts β-catenin in cilia to facilitate nuclear translocation	+	[64, 291]	[292]
CACNA1C (Timothy syndrome)	voltage-gated L-type calcium channel alpha 1C subunit	Encodes the alpha-1 subunit of a voltage-dependent calcium channel, which mediates calcium ion entry into excitable cells
DHCR7 (Smith- Lemli-Opitz syndrome)	7-dehydrocholesterol reductase	Encodes the final enzyme in the cholesterol biosynthetic pathway	+	[293]
FMR1 (Fragile X syndrome)	fragile X mental retardation 1	Encodes Fragile X mental retardation protein, an RNA- binding protein that trafficks target mRNAs from the nucleus to the cytoplasm	+	[59]	[294]
MECP2 (Rett syndrome)	methyl CpG binding protein 2	Encodes MeCP2, which binds methylated DNA to recruit repressor complexes for gene repression; may also activate some genes	+	[295]	[296]
NF1 (Neurofibromatosis 1)	neurofibromin isoform 1	Encodes neurofibromin, a GTP-ase activator and negative regulator of the RAS signaling pathway	+	[297]	[298]
PTEN (Cowden disease)	phosphatase and tensin homolog	Encodes a protein tyrosine phosphatase, which negatively regulates the PI3K–AKT–mTOR pathway	+	[299]	[300]
TSC1,2 (Tuberous Sclerosis types I and II)	tuberous sclerosis 1 and 2	Encodes a complex, which negatively regulates the mTOR pathway	+	[60]	[301]
UBE3A (Angelman syndrome)	ubiquitin protein ligase E3A	Encodes a ubiquitination ligase, which targets protein degradation system		[302]	[303]
Rare Mutations (Structural Variations)
GABRB3 (15q11–13 duplication)	GABAA receptor beta 3	Encodes one of 18 subunits for a multisubunit chloride channel which forms the GABAA receptor	+	[70]	[71]
SHANK3 (22q13 deletion)	SH3 and multiple ankyrin repeat domains 3	Encodes a multidomain scaffold protein of the postsynaptic density that connects neurotransmitter receptors, ion channels, and other proteins to the actin cytoskeleton and G-protein coupled signaling pathways.	+	[61, 62] SHANK3 – Not determined	Shank3 – Not determined
SEZ6L2 (16p11.2 deletion)	seizure related 6 homolog	Encodes a multidomain transmembrain protein, homologous to SRPX2 in which mutations cause epilepsy and language disorders
NLGN3	neuroligin 3	Encodes a member of the neuroligin family of neuronal surfact proteins, which are ligands for beta- neurexins and may be involved in synapse formation and remodeling
NLGN4X	neuroligin 4, X-linked	Encodes a member of the neuroligin family of neuronal surfact proteins, which are ligands for beta- neurexins and may be involved in synapse formation and remodeling
NRXN1	neurexin 1	Encodes a member of the neurexin family of cell adhesion molecules and receptors located on the neuronal cell surface; may be involved in cell recognition and adhesion by forming intracellular junctions through neuroligin binding	+		[304]
Association Studiesa
AVPR1Aa	arginine vasopressin receptor 1A	Encodes a G-protein coupled receptor for arginine vasopression, which activate a phosphatidyl- inositol-calcium second messenger system; involved in social behaviors
CNTNAP2	contactin associated protein- like 2	Encodes Caspr2, a neurexin family member; homozygous mutations cause cortical dysplasia-focal epilepsy syndrome	+	[305]
DISC1	disrupted in schizophrenia 1	Encodes a large transmembrane protein involved in neurite outgrowth and cortical development
EN2a	engrailed 2	Encodes a Homeobox protein critical for hindbrain patterning	+		[68]
GRIK2	ionotropic glutamate receptor, kainate 2	Encodes a postsynaptic glutamatereceptor subunit; homozygous mutationscause a mental retardation syndrome	+		[306]
ITGB3a	integrin beta-3 precursor	Encodes a cell-surface protein composed of an alpha and beta chain to mediate cell adhesion and cell-surface mediated signaling of platelets
METa	met proto-oncogene	Encodes a receptor tyrosine kinase involved in cell proliferation, morphogenesis and survival; influences synapse development	+		[69]
OXTR*	oxytocin receptor	Encodes a G-protein coupled receptor for oxytocin; involved in social behaviors
RELN	reelin	Encodes a large secreted extracellular matrix protein involved in cell-cell interactions required for proper cell positioning and neuronal migration in brain development	+	[142, 307]	[308]
SLC25A12	calcium-binding mitochondrial carrier protein	Encodes a calcium-binding mitochondrial carrier protein, which is involved in exchanging aspartate for glutamate across the inner mitochondrial membrane			[309]
SLC6A4	serotonin transporter	Encodes the serotonin transporter, an integral membrane protein that transports serotonin from the synaptic cleft into presynaptic neurons

^aFive or more positive association studies (https://sfari.org/sfari-gene, accessed 27 May 2011)

^bPresence of cerebellar effects in humans and/or mice: (blank) if no information available