Comment on “Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients”

Eran, Alal; Graham, Kaitlin R.; Vatalaro, Kayla; McCarthy, Jill; Collins, Christin; Peters, Heather; Brewster, Stephanie; Hanson, Ellen; Hundley, Rachel; Rappaport, Leonard; Holm, Ingrid A.; Kohane, Isaac S.; Kunkel, Louis M.

doi:10.1172/jci38620

Cited by 10 publications

(13 citation statements)

References 1 publication

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“…Exon 3-skipped CADPS2 protein possesses almost normal BDNF releasing activity but is not properly transported into the axons of neocortical or cerebellar neurons. However, Eran et al [2009] observed no difference in prevalence of exon 3 skipping between ASDs and control samples. They concluded that exon 3 skipping represents a normal, minor isoform of CADPS2 in the cerebellum and is likely not a mechanism underlying autism susceptibility or pathogenesis.…”

Section: Discussionmentioning

confidence: 63%

Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV

Okamoto¹,

Hatsukawa²,

Shimojima³

et al. 2011

American J of Med Genetics Pt A

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We performed array comparative genomic hybridization utilizing a whole genome oligonucleotide microarray in a patient with the autism spectrum disorders (ASDs) and persistent hyperplastic primary vitreous (PHPV). Submicroscopic deletions in 7q31 encompassing CADPS2 (Ca(2+) -dependent activator protein for secretion 2) and TSPAN12 (one of the members of the tetraspanin superfamily) were confirmed. The CADPS2 plays important roles in the release of neurotrophin-3 and brain-derived neurotrophic factor. Mutations in TSPAN12 are a relatively frequent cause of familial exudative vitreoretinopathy. We speculate that haploinsufficiency of CADPS2 and TSPAN12 contributes to ASDs and PHPV, respectively.

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Section: Discussionmentioning

confidence: 63%

Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV

Okamoto¹,

Hatsukawa²,

Shimojima³

et al. 2011

American J of Med Genetics Pt A

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“…We are currently investigating the association of these variants with exon 3 skipping. We must also consider the possibility that there is a polymorphism(s) in an unknown gene(s), which alters the splicing of CAPS2 mRNA (10). This scenario would predict the abnormal splicing of multiple genes besides CAPS2.…”

Section: Discussionmentioning

confidence: 99%

“…Our subsequent knockout mouse study showed that Caps2 not only plays a role in neuronal development of the cerebrum and hippocampus as well as the cerebellum, but that it is also associated with social interaction, anxiety, and maternal and circadian behaviors in mice (7,8). We also showed that the expression of an exon 3-skipped (or -spliced out) form of CAPS2 (designated CAPS2-dex3) (8), which is now known to be a rare alternative splicing variant (9,10), is increased in a subgroup of patients with autism and is not properly localized in axons (8). Thus, neurons overexpressing dex3 may fail to coordinate local BDNF release from axons properly (8,9), resulting in improper brain development and function.…”

mentioning

confidence: 90%

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice

Sadakata

Shinoda

Oka

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Ca 2+-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in socialand anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNFmediated coordination of brain development to autism-related behaviors and patient genotype.-dependent activator protein for secretion 2 (CAPS2 or CADPS2) is a member of the CAPS protein family that regulates the trafficking of dense-core vesicles by binding both phosphoinositides and dense-core vesicles (1-5). We initially identified mouse Caps2 as a potent factor promoting the release of brain-derived neurotrophic factor (BDNF) during cerebellar development (6, 7). Our subsequent knockout mouse study showed that Caps2 not only plays a role in neuronal development of the cerebrum and hippocampus as well as the cerebellum, but that it is also associated with social interaction, anxiety, and maternal and circadian behaviors in mice (7,8). We also showed that the expression of an exon 3-skipped (or -spliced out) form of CAPS2 (designated CAPS2-dex3) (8), which is now known to be a rare alternative splicing variant (9, 10), is increased in a subgroup of patients with autism and is not properly localized in axons (8). Thus, neurons overexpressing dex3 may fail to coordinate local BDNF release from axons properly (8, 9), resulting in improper brain development and function. The human CAPS2 gene locus (7q31.32) is intriguingly located within the autism susceptibility locus 1 (AUTS1) (11) on chromosome 7q31-q33, one of several susceptibility loci for autism (12). Moreover, an association of CAPS2 with autism has been suggested recently, not only by the presence of copy number variations in the CAPS2 gene in autistic patients (13-15), but also by decreased transcription of CAPS2 in the brains of people with autism (16). Thus, clarifying the biological significance of dex3 expression is an important step in elucidating the association of CAPS2 with brain circuit development and behaviors related to autism.The potential molecular risk factors for autism susceptibility have been increasingly reported (17-26) but are poorly characterized in animal models. In this report, we generated a mouse model expressing dex3 and analyzed the cellular and autistic-like behavioral phenotypes of dex3 mice. Our results support the involvement of the rare dex3 form of Caps2 in defective axonal BDNF secretion, affecting proper brain circuit development and/ or functio...

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“…ment by Eran et al (1) regarding our recently published CADPS2 article in the JCI (2). We appreciate their comment that "exon 3 skipping likely represents a minor isoform rather than aberrant splicing" in the blood and postmortem cerebella of both healthy and autistic individuals.…”

mentioning

confidence: 84%

“…1) and claimed that only one sample (control sample C14) was homozygous in their study. Little quantitative gain is generally noticed when increasing the number of cycles to such an extraordinary number.…”

mentioning

confidence: 98%

Response to the letter by Eran et al.

Furuichi¹,

Sadakata

2009

J. Clin. Invest.

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Comment on “Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients”

Cited by 10 publications

References 1 publication

Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV

Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice

Response to the letter by Eran et al.

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