Human Disease Model Report: neurodevelopmental disorder with severe developmental delay, intellectual disability, and behavioral abnormalities, CYFIP1-related

General Information

Name

neurodevelopmental disorder with severe developmental delay, intellectual disability, and behavioral abnormalities, CYFIP1-related

FlyBase ID

FBhh0001552

Disease Ontology Term

syndromic intellectual disability

Parent Disease

OMIM

Overview

This report describes neurodevelopmental disorder with severe developmental delay, intellectual disability, and behavioral abnormalities, CYFIP1-related. The human gene implicated is CYFIP1, which encodes cytoplasmic FMR1 interacting protein 1, and is one of the four genes within the 15q11.2 deletion associated with chromosome 15q11.2 deletion syndrome (FBhh0001124). There is one high-scoring fly ortholog, Dmel\Cyfip, for which null alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Additionally, knock-in alleles of Dmel\Cyfip bearing missense mutations orthologous to variants implicated in human disease have been generated. See the 'Disease-Implicated Variants' table below.

The human gene Hsap\CYFIP1 has been introduced into flies, but has not been characterized.

Homozygous null mutations of Dmel\Cyfip are lethal at pupal stages, while flies bearing homozygous or biallelic knock-in alleles bearing disease-implicated variants survive to adulthood. Cells of flies bearing the variant alleles exhibit actin cytoskeleton deficits similar to those observed in affected human fibroblasts. Flies homozygous or biallelic for the missense variant alleles exhibit changes in the axonal arborization patterns of sLNv neurons, as well as subtle changes to the morphology of the adult mushroom and ellipsoid bodies. Affected male adults also exhibit changes in social and motor behavior. (FBrf0258391).

[updated Apr. 2024 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: neurodevelopmental disorder with severe developmental delay, intellectual disability, and behavioral abnormalities, CYFIP1-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Two individuals in a nonconsanguineous family are affected by a severe neurodevelopmental disorder, exhibiting developmental delay, intellectual disability, generalized nonmotor seizures,autism spectrum disorder, spastic tetraparesis, microcephaly, and brain morphology defects (Mariano, et al., 2024, pubmed:37704042, FBrf0258391).

(FlyBase Curators, 2013-)

Genetics

This autosomal recessive disorder has been associated with a biallelic combination of two pathogenic missense variants of the human gene CYFIP1 (Mariano, et al., 2024, pubmed:37704042, FBrf0258391).

(FlyBase Curators, 2013-)

Cellular phenotype and pathology

Cultured skin fibroblasts from an affected individual, when labeled with phalloidin-TRITC, display a reduction in phalloidin intensity when compared those of unaffected family members or healthy volunteers. Phalloidin-TRITC binds filamentous (F) actin; a reduction in intensity indicates a decrease in F-actin. Fibroblasts from the affected individual display an increase in aspect ratio (major axis/minor axis), accompanied by a subtle change in cell morphology (Mariano, et al., 2024, pubmed:37704042, FBrf0258391).

(FlyBase Curators, 2013-)

Molecular information

Through physical interaction with RAC1, CYFIP1 activates the WAVE regulatory complex and promotes cytoskeletal remodeling, a key aspect of dendritic spine formation. CYFIP1 also binds to the fragile X mental retardation protein, forming a translational inhibitory complex. (Woo et al. 2019, pubmed:31202490 and references therein, FBrf0243072.)

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): CYFIP1
Gene Cards: CYFIP1
MedlinePlus (gene): CYFIP1
MARRVEL (human gene): CYFIP1
NCBI (Entrez) gene: CYFIP1; cytoplasmic FMR1 interacting protein 1

Disease synonyms

Related Diseases

Related human health report(s)

chromosome 15q11.2 deletion syndrome

Ortholog Information

Human gene(s) in FlyBase

Hsap\CYFIP1

Human gene (HGNC)

Symbol / Name

CYFIP1; cytoplasmic FMR1 interacting protein 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Cyfip

(DIOPT, 2013-)

Comments on ortholog(s)

Two to one (2 human to 1 Drosophila); CYFIP1 has one high-scoring Drosophila ortholog, Cyfip.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Cyfip

Gene Snapshot

Cytoplasmic FMR1 interacting protein (Cyfip) encodes an essential protein that is a component of the WAVE actin nucleator complex. It controls actin cytoskeleton remodeling and interacts with the products of Fmr1 and Rac1. It controls morphogenesis and synapse organization. [Date last reviewed: 2020-07-09]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human CYFIP1 and CYFIP2 (1 Drosophila to 2 human).

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (11 groups)

Cyfip

protein-protein

Interacting group

Assay

References

Cyfip - Abi

anti bait coimmunoprecipitation, peptide massfingerprinting

(Gautier et al., 2011)

Cyfip - Abl

pull down, Identification by mass spectrometry

(Cheong et al., 2020)

Cyfip - Arf1

pull down, western blot

(Humphreys et al., 2012)

Cyfip - Chc

anti bait coimmunoprecipitation, peptide massfingerprinting

(Gautier et al., 2011)

Cyfip - drk

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Cyfip - Fmr1

anti bait coimmunoprecipitation, western blot, pull down, autoradiography

(Bozzetti et al., 2015, Schenck et al., 2003)

Cyfip - Hem

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, peptide massfingerprinting, two hybrid, experimental knowledge based

(Gautier et al., 2011, Guruharsha et al., 2011, Bogdan et al., 2004, Schenck et al., 2004)

Cyfip - HSPC300

anti bait coimmunoprecipitation, western blot, pull down, molecular sieving, molecular weight estimation by staining

(Chaudhari et al., 2024, Chen et al., 2014, Chia et al., 2014, Gautier et al., 2011, Ismail et al., 2009, Qurashi et al., 2007)

Cyfip - Rac1

anti bait coimmunoprecipitation, western blot

(Schenck et al., 2003)

Cyfip - SCAR

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Gautier et al., 2011, Guruharsha et al., 2011, Schenck et al., 2004)

Cyfip - WASp

pull down, western blot