Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders - PubMed (original) (raw)

doi: 10.1038/ng1933. Epub 2006 Dec 17.

Catalina Betancur, Tobias M Boeckers, Juergen Bockmann, Pauline Chaste, Fabien Fauchereau, Gudrun Nygren, Maria Rastam, I Carina Gillberg, Henrik Anckarsäter, Eili Sponheim, Hany Goubran-Botros, Richard Delorme, Nadia Chabane, Marie-Christine Mouren-Simeoni, Philippe de Mas, Eric Bieth, Bernadette Rogé, Delphine Héron, Lydie Burglen, Christopher Gillberg, Marion Leboyer, Thomas Bourgeron

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

Christelle M Durand et al. Nat Genet. 2007 Jan.

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.

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Figures

Figure 1

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

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.

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