The TANC2 gene encodes a Tetratricopeptide repeat, ankyrin repeated and coiled-coil containing protein 2 (OMIM*615047) located on chromosome 17q23.2-q23.3. TANC2 is a large synapse protein (200kDa) and it contains a P-loop ATPase domain in the N-terminus, ankyrin (ANK) repeat containing domain, a tetratricopeptide (TRP) repeats region, and a PDZ binding motif in the C-terminus.
TANC2 is a synapse scaffolding protein that interacts with multiple post-synaptic density proteins to regulate dendritic spines and excitatory synapse formation. TANC2 is broadly expressed in human developing brain, in particular in excitatory neurons and radial glia cells; Tanc2 knockdown increases mTOR activity in human neural progenitor cell and neurons.
In literature, 28 clinically relevant single nucleotide and copy number variants have been clearly associated with NDDs. The likely disrupting single nucleotide variants, comprising 8 frameshift, 5 stop, 5 canonical splice sites, are scattered throughout the gene, while the missense variants localize in the ATPase domain (p.R755H, p.R760C, p.A794V), in the ANK domain (p.R961Q) and in the C-terminal region of the protein (p.H1689R).
A functional study demonstrated that the p.R760C variant impairs the binding with KIF1A and the recruitment of KIF1A-transported vesicles in neurons. Moreover, the p.R1066* failed to accumulate at the dendritic spines, suggesting an important role of the C-terminal PDZ binding motif for TANC2 synaptic localization.
Variants and gene alterations in the TANC2 gene may be identified by ID/ASD targeted gene panels, Whole Exome Sequencing; CNV may be detected by array CGH analysis.
TANC2