Association study of SHANK3 gene polymorphisms with autism in Chinese Han population

Qin, Jian; Jia, Mengmeng; Wang, Lifang; Lu, Tianlan; Ruan, Yan; Liu, Jing; Guo, Yanqing; Zhang, Jishui; Yang, Xiaoling; Yue, Weihua; Zhang, Dai

doi:10.1186/1471-2350-10-61

Cited by 29 publications

(14 citation statements)

References 32 publications

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“…These results are partially confirmed by recent studies that did not find any SHANK3 alterations in cohorts of patients with AD. 47,48 Notably, no other gene variants have ever been found with a frequency as high as the one shown in PDD-NOS, making SHANK3 the most relevant candidate gene for these cases.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141Ala), and a splicing mutation (c.1820-4 G4A). Additionally, in 17 patients (7.7%) we detected a c.1304 þ 48C4T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.Ala1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304 þ 48C4T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients.

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Section: Discussionmentioning

confidence: 99%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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“…37 (Although the function of SHANK3 has not been consistently replicated by all studies. 38,39 ) In this process, SHANK3 interacts with cortactin, a protein implicated in connecting the actin network sites with receptor signaling complexes. 40 On the basis of these findings, one could speculate that DIAPH3 operates downstream of SHANK3 regulation.…”

Section: Discussionmentioning

confidence: 99%

A double hit implicates DIAPH3 as an autism risk gene

et al. 2010

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Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a ‘double-hit’ compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

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“…Two possibly causative SHANK3 mutations were also found in a screen of 427 ASD patients [Gauthier et al, 2009]. However, no SHANK3 copy number variants or SNP associations were seen in 330 multiplex ASD families in another study [Sykes et al, 2009], nor was a SHANK3 SNP association seen in screening 305 Chinese Han trios [Qin et al, 2009], although neither of these studies sequenced the gene. A screen of 396 patients with ASD and 184 patients with intellectual impairment revealed 2 individuals with deletions in SHANK2 associated with both ASD and intellectual impairment.…”

Section: Shank3mentioning

confidence: 99%

The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)

Phelan

McDermid²

2011

Mol Syndromol

384

320

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The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. In addition to normal growth and a constellation of minor dysmorphic features, this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia. In addition, more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD). The differential diagnosis includes Angelman syndrome, velocardiofacial syndrome, fragile X syndrome, and FG syndrome. Over 600 cases of 22q13.3 deletion syndrome have been documented. Most are terminal deletions of ∼100 kb to >9 Mb, resulting from simple deletions, ring chromosomes, and unbalanced translocations. Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. Two mouse knockout models and cell culture experiments show that SHANK3 is involved in the structure and function of synapses and support the hypothesis that the majority of 22q13.3 deletion syndrome neurological defects are due to haploinsufficiency of SHANK3, although other genes in the region may also play a role in the syndrome. The molecular connection to ASD suggests that potential future treatments may involve modulation of metabotropic glutamate receptors.

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Association study of SHANK3 gene polymorphisms with autism in Chinese Han population

Cited by 29 publications

References 32 publications

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

A double hit implicates DIAPH3 as an autism risk gene

The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)

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