Review articleSHANK3 as an autism spectrum disorder-associated gene
Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two main phenotypic expressions: impairments in reciprocal interaction and communication and restricted and stereotyped patterns of interests and behaviors (reviewed in Ref. [1]). ASD affects about 1–2% of children, and it is about four times more common in males than in females. Although the causative genes of ASD remain largely unknown, familial and twin studies have indicated that ASD is a genetic disorder. Structural chromosome variants have been identified in some individuals with ASD, the most common being deletions and duplications on chromosome 7q, 15q, and 22q. In this review we focused on a syndromic developmental disorder that is characterized by a terminal deletion of the 22q segment, called 22q13.3 deletion syndrome.
Section snippets
22q13.3 Deletion syndrome
A terminal 22q13.3 deletion is one of the common submicroscopic subtelomere deletions found in patients with developmental disorder. The loss of 22q13.3 results from simple deletion, translocation, ring chromosome formation and rare structural changes in a long arm of chromosome 22. The 22q13.3 deletion syndrome (Phelan–McDermid syndrome) is a recognizable malformation syndrome characterized by severe expressive language and speech delay, hypotonia, global development delay, normal to advanced
Etiology of the 22q13.3 deletion syndrome
Genetic studies were currently performed to identify the gene that was responsible for the 22q13.3 deletion syndrome, and one gene was considered definite candidate. In 2001, Bonaglia et al. [4] identified a boy with all of the features of 22q13.3 deletion syndrome. Genetic analysis showed a translocation; 46, XY, t(12;22)(q24.1;q13.3), and sequence analysis identified the breakpoint on chromosome 22 at position 296489/296494, which is within exon 21 of the human homologue of rat proline-rich
Association between SHANK3 and ASD
The SHANK3 gene consists of 22 exons and encodes a multidomain protein that contains ankyrin repeats (ANK), an Src homology 3 (SH3) domain, a postsynaptic density 95/discs large/zone occludens-1 (PDZ) domain, a proline-rich region, a homer-binding region, a cortactin-binding region and a sterile alpha motif (SAM) (Figs. 1a and Fig. 2a) [6]. The SHANK3 is abundantly expressed in the heart and moderately expressed in the brain and spleen [7]. In the brain, SHANK3 is mainly expressed in neurons,
Epigenetic regulation of SHANK3 expression
Recently, five CpG islands in the SHANK3 gene were identified by whole-genome screening for tissue-specific differential methylation (Fig. 2a) [21]. DNA methylation at CpG dinucleotides is a post replication event that is essential to a properly functioning genome. Beri et al. [22] analyzed DNA methylation of CpG-islands in the SHANK3 gene, and indicated that tissue-specific expression of SHANK3 was regulated by an epigenetic mechanism of DNA methylation, especially that the methylation of
Shank3 mutant mice as mouse models of ASD
Genetically modified mice are useful tools for investigating gene function. Several lines of Shank3-deficient mice have been generated and used to investigate the contribution of SHANK3 to the neuropathology of ASD. Bozdagi et al. [25] were the first to report generating Shank3 deficient mice with a targeted disruption from exon 4 to exon 9, which encodes the ankyrin repeats domain. The deficiency resulted in a disruption of a full-length of SHANK3 protein. The heterozygous mice (Shank3+/−)
Conclusions
Haploinsufficiency of the SHANK3 gene, which encodes a synaptic scaffolding protein, is thought to be responsible for the 22q13.3 deletion syndrome characterized by severe expressive language and speech delay, hypotonia, global developmental delay and autistic behavior. Recent genetic studies have indicated that, in addition to the haploinsufficiency of SHANK3 gene, several SHANK3 mutations cause neuronal developmental disorders, including ASD, and psychiatric disorders. Several variants of
Acknowledgments
We are thankful to Dr. Shinichi Kohsaka providing valuable suggestions.
The contents of this paper was presented at the “Exploring Autism Research Collaboration between Japan and United States Joint Academic Conference on Autism Spectrum Disorders”, Tokyo, Japan, December 1–3, 2011.
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Present address: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.