Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

Abstract

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. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

Figure 1

Genetic analyses of three families with ASD and SHANK3 mutations, (a) In family ASD 1, the proband carries a de novo terminal deletion of the paternal chromosome 22q13. The deletion breakpoint is located in intron 8 of SHANK3. The breakpoint was sequenced after amplification of the proband DNA using primer 1 in SHANK3 and primer 2 in the telomeric repeats. The heterogenous smear in the proband is likely due to the difference in telomere length from chromosome to chromosome and/or priming at different locations by the telomeric primer, (b) In family ASD 2, the two probands carry the same de novo SHANK3 frame-shift mutation on the maternal chromosome 22q13. The mutation is absent from the mother blood and buccal cells, suggesting a germinal mosaicism. The guanine insertion is located in exon 21 of SHANK3, leading to a premature truncated protein, (c) In family ASD 3, the father carries a balanced translocation t(14,22)(p11.2;q13.33), proband A (Asperger syndrome) presents a partial 22qter trisomy and proband B (autism) has a 22qter deletion, (d) Using quantitative fluorescent PCR, we mapped the breakpoint between the genes ALG12 and MLC1. The dosage quotient has a theoretical value of 0.5 for a deletion and 1.5 for a duplication.

Figure 2

Localization of rare nonsynonymous variations or truncating SHANK3 mutations identified in families with ASD. ANK: ankyrin repeats; SH3: Src homology 3 domain; PDZ: postsynaptic density 95/Discs large/zona occludens-1 homology domain; SAM: sterile alpha motif domain.