Disease relevance of SHANK3

• This ProSAP2/Shank3 haploinsufficiency may cause a syndrome that is characterized by severe expressive language delay, mild mental retardation and minor facial dysmorphisms [1].
• The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome [2].

Psychiatry related information on SHANK3

• Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders [3].
• SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome [3].

High impact information on SHANK3

• Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3 [4].
• Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene [2].
• Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum [2].
• ProSAP2/Shank3, cortactin and Ena/VASP-IRs were concentrated on the cytoplasmic face of the PSD, at the level of the PSD projections [5].
• Coexpression of shank3 abrogates branch formation and targets Densin-180 into postsynaptic clusters instead [6].

Biological context of SHANK3

• The molecular structure of SHANK3 was further characterised [7].
• Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins [8].
• This study supports this candidate gene by identifying a phenotypically normal r(22) individual whose ring chromosome does not disrupt SHANK3 [9].
• Loss of the SHANK3/PROSAP2 gene has been proposed to be responsible for the main neurological developmental deficits observed in 22q13 monosomies [9].

Disease relevant mouse models of SHANK3

• Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism [10].

Anatomical context of SHANK3

• ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses [2].

References