Dataset Information

Domain-Specific Cognitive Impairments in Humans and Flies With Reduced CYFIP1 Dosage.

ABSTRACT: BACKGROUND:Deletions encompassing a four-gene region on chromosome 15 (BP1-BP2 at 15q11.2), seen at a population frequency of 1 in 500, are associated with increased risk for schizophrenia, epilepsy, and other common neurodevelopmental disorders. However, little is known in terms of how these common deletions impact cognition. METHODS:We used a Web-based tool to characterize cognitive function in a novel cohort of adult carriers and their noncarrier family members. Results from 31 carrier and 38 noncarrier parents from 40 families were compared with control data from 6530 individuals who self-registered on the Lumosity platform and opted in to participate in research. We then examined aspects of sensory and cognitive function in flies harboring a mutation in Cyfip, the homologue of one of the genes within the deletion. For the fly studies, 10 or more groups of 50 individuals per genotype were included. RESULTS:Our human studies revealed profound deficits in grammatical reasoning, arithmetic reasoning, and working memory in BP1-BP2 deletion carriers. No such deficits were observed in noncarrier spouses. Our fly studies revealed deficits in associative and nonassociative learning despite intact sensory perception. CONCLUSIONS:Our results provide new insights into outcomes associated with BP1-BP2 deletions and call for a discussion on how to appropriately communicate these findings to unaffected carriers. Findings also highlight the utility of an online tool in characterizing cognitive function in a geographically distributed population.

SUBMITTER: Woo YJ

PROVIDER: S-EPMC6679746 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Domain-Specific Cognitive Impairments in Humans and Flies With Reduced CYFIP1 Dosage.

Woo Young Jae YJ Kanellopoulos Alexandros K AK Hemati Parisa P Kirschen Jill J Nebel Rebecca A RA Wang Tao T Bagni Claudia C Abrahams Brett S BS

Biological psychiatry 20190417 4

<h4>Background</h4>Deletions encompassing a four-gene region on chromosome 15 (BP1-BP2 at 15q11.2), seen at a population frequency of 1 in 500, are associated with increased risk for schizophrenia, epilepsy, and other common neurodevelopmental disorders. However, little is known in terms of how these common deletions impact cognition.<h4>Methods</h4>We used a Web-based tool to characterize cognitive function in a novel cohort of adult carriers and their noncarrier family members. Results from 31 ...[more]

PMID: 31202490

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Project description:Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.

Dataset Information

Domain-Specific Cognitive Impairments in Humans and Flies With Reduced CYFIP1 Dosage.

Publications

Domain-Specific Cognitive Impairments in Humans and Flies With Reduced CYFIP1 Dosage.

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