Human Disease Model Report: Vissers-Bodmer syndrome

General Information

Name

Vissers-Bodmer syndrome

FlyBase ID

FBhh0001252

Disease Ontology Term

Vissers-Bodmer syndrome

Parent Disease

OMIM

VISSERS-BODMER SYNDROME; VIBOS

Overview

This report describes Vissers-Bodmer syndrome, a newly defined and variable neurodevelopmental syndrome caused by heterozygous mutations in the CNOT1 gene. The CNOT1 gene is a component of the CCR4-NOT complex, which has roles in transcriptional regulation, RNA deadenylation, and protein ubiquitination. There is a single orthologous gene in Drosophila, Not1, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and overexpression constructs have been generated.

UAS constructs of the human Hsap\CNOT1 have been introduced into flies, including wild-type and variants implicated in disease. Heterologous rescue (functional complementation) by the wild-type human gene has been demonstrated for the memory and learning-loss phenotypes of Not1 RNAi-effected loss-of-function genotypes. Nine variants (see table below), including 2 loss-of-function variants and 7 missense variants and all targeting different functional domains, were assessed for ability to rescue the Not1 phenotypes. Eight failed to rescue or only partially rescued the memory phenotypes.

Animals with RNA-effected loss-of-function of Dmel\Not1 specifically in the mushroom body of the brain or pan-neuronally in the adult stage exhibit memory and learning-loss phenotypes. Pan-neuronal knockdown prior to adulthood results in lethality.

See also the FlyBase gene group report CCR4-NOT COMPLEX (FBgg0000469). Genetic and physical interactions have been described for Dmel\Not1 see below and in the Not1 gene report.

[updated Oct. 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: Vissers-Bodmer syndrome

OMIM report

[VISSERS-BODMER SYNDROME; VIBOS](https://omim.org/entry/619033)

Human gene(s) implicated

[CCR4-NOT TRANSCRIPTION COMPLEX, SUBUNIT 1; CNOT1](https://omim.org/entry/604917)

Symptoms and phenotype

Vissers-Bodmer syndrome (VIBOS) is characterized by global developmental delay with variably impaired intellectual development, speech delay, motor delay, and behavioral abnormalities apparent from infancy. The phenotype is highly variable: some individuals have only mild learning difficulties, whereas others have severe cognitive impairment with IQ in the 50s. Many patients have behavioral abnormalities, including autism spectrum disorder, ADD, ADHD, obsessive-compulsive disorder, and impulsivity. Other common features include growth impairment abnormalities, hypotonia, and distal skeletal defects, such as foot and hand deformities. Less common features include seizures, brain abnormalities on MRI, feeding problems, and joint hypermobility. Most individuals have dysmorphic facial features, but there is no recognizable gestalt (summary by Vissers et al., 2020; pubmed:32553196). [from MIM:619033; 2020.10.13]

(OMIM, 2013-)

Individuals with a CNOT1 variant show a broad phenotypic spectrum. The most consistent features observed included intellectual disability (ID) (72%) of varying degree, development delay (DD) (92%), speech delay (83%), motor delay (83%), and hypotonia (74%). [FBrf0246104]

(FlyBase Curators, 2013-)

Genetics

Identified individuals were heterozygous for the CNOT1 variant. In most cases, the variant had occurred de novo; in a few cases the variant was inherited from a mildly affected or mosaic mother (FBrf0246104).

(FlyBase Curators, 2013-)

Vissers-Bodmer syndrome (VIBOS) is caused by heterozygous mutation in the CNOT1 gene. [from MIM:619033; 2020.10.13]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

CNOT1 encodes a scaffolding component of the CCR4-NOT Transcription Complex. [Gene Cards, CNOT1; 2020.08.29]

(FlyBase Curators, 2013-)

The CCR4-NOT complex is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. CNOT1 is the central scaffolding protein of the complex, (in)directly binding to all CCR4-NOT partners. In addition to its scaffolding function, CNOT1 has been considered as a translational regulator through the binding of nuclear receptors and as a regulator of RNA deadenylase activity (FBrf0246104 and references cited therein).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): CNOT1
Gene Cards: CNOT1
MedlinePlus (gene): CNOT1
MARRVEL (human gene): CNOT1
NCBI (Entrez) gene: CNOT1; CCR4-NOT transcription complex subunit 1

Disease synonyms

neurodevelopmental syndrome with intellectual disability, developmental and motor delay, speech delay, seizures, hypotonia, and behavioral disturbances, CNOT1-related

VIBOS

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Hsap\CNOT1

Human gene (HGNC)

Symbol / Name

CNOT1; CCR4-NOT transcription complex subunit 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Not1

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human gene to 1 Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Not1

Gene Snapshot

Not1 (Not1) encodes a poly(A)-specific ribonuclease involved in translation inhibition and ovarian follicle cell development. [Date last reviewed: 2019-08-01]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

CCR4-NOT

Comments on ortholog(s)

High-scoring ortholog of human CNOT1 (1 Drosophila to 1 human. Dmel\Not1 shares 46% identity and 62% similarity with the human gene.

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 (28 groups)

Not1

RNA-protein

Interacting group

Assay

References

Not1 - bel

clip-seq

(Kotov et al., 2020)

protein-protein

Interacting group

Assay

References

Not1 - Atx2

anti bait coimmunoprecipitation, western blot

(Lee et al., 2017)

Not1 - aub

anti tag coimmunoprecipitation, western blot

(Rojas-Ríos et al., 2017)

Not1 - bam

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

(Sgromo et al., 2018)

Not1 - cu

anti bait coimmunoprecipitation, anti tag western blot

(Temme et al., 2010)

Not1 - cup

anti tag coimmunoprecipitation, anti tag western blot

(Igreja and Izaurralde, 2011)

Not1 - gw

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot

(Huntzinger et al., 2013, Braun et al., 2011)

Not1 - Gyf

anti tag coimmunoprecipitation, anti tag western blot

(Ruscica et al., 2019)

Not1 - Helz

anti tag coimmunoprecipitation, anti tag western blot

(Hanet et al., 2019)

Not1 - Marf

colocalization, fluorescence microscopy, inferred by author

(Salgania et al., 2024)

Not1 - Marf1

anti tag coimmunoprecipitation, western blot

(Zhu et al., 2018)

Not1 - me31B

anti tag coimmunoprecipitation, western blot

(Lee et al., 2017)

Not1 - nanos

anti tag coimmunoprecipitation, anti tag western blot, colocalization, fluorescence microscopy, inferred by author, pull down, molecular weight estimation by staining, western blot

(Salgania et al., 2024, Arvola et al., 2020, Raisch et al., 2016)

Not1 - Not3

molecular sieving, molecular weight estimation by staining, colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry, experimental knowledge based, western blot

(Pekovic and Wahle, 2024, Salgania et al., 2024, Arvola et al., 2020, Bawankar et al., 2013, Guruharsha et al., 2011, Temme et al., 2010)

Not1 - Not10

anti tag coimmunoprecipitation, anti tag western blot

(Bawankar et al., 2013)

Not1 - Not11

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

(Haugen et al., 2022, Bawankar et al., 2013)

Not1 - piwi

anti bait coimmunoprecipitation, western blot

(Kordyukova et al., 2020)

Not1 - Pop2

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot, colocalization, fluorescence microscopy, inferred by author, molecular sieving, molecular weight estimation by staining, experimental knowledge based, Identification by mass spectrometry

(Pekovic and Wahle, 2024, Salgania et al., 2024, Bawankar et al., 2013, Petit et al., 2012, Guruharsha et al., 2011, Temme et al., 2010)

Not1 - Pos

anti tag coimmunoprecipitation, anti tag western blot

(Xia et al., 2022)

Not1 - pum

anti tag coimmunoprecipitation, anti tag western blot, western blot, two hybrid

(Haugen et al., 2022, Arvola et al., 2020)

Not1 - Rcd-1

molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, colocalization, fluorescence microscopy, inferred by author

(Pekovic and Wahle, 2024, Salgania et al., 2024, Xia et al., 2022, Bawankar et al., 2013)

Not1 - Rga

molecular sieving, molecular weight estimation by staining, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, colocalization, fluorescence microscopy, inferred by author, Identification by mass spectrometry, experimental knowledge based

(Pekovic and Wahle, 2024, Salgania et al., 2024, Arvola et al., 2020, Bawankar et al., 2013, Guruharsha et al., 2011, Temme et al., 2010)

Not1 - rictor

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Not1 - roq

anti tag coimmunoprecipitation, anti tag western blot, colocalization, fluorescence microscopy, inferred by author

(Salgania et al., 2024, Sgromo et al., 2017)

Not1 - RpL10Ab

pull down, western blot

(Antic et al., 2015)

Not1 - smg

tandem affinity purification, Identification by mass spectrometry, two hybrid

(Pekovic et al., 2023, Semotok et al., 2005)

Not1 - thoc5

anti bait coimmunoprecipitation, western blot

(Kordyukova et al., 2020)

Not1 - twin

anti tag coimmunoprecipitation, anti tag western blot, experimental knowledge based, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry, molecular sieving, molecular weight estimation by staining

(Pekovic and Wahle, 2024, Kordyukova et al., 2020, Morgunova et al., 2015, Bawankar et al., 2013, Joly et al., 2013, Guruharsha et al., 2011, Temme et al., 2010)

Alleles Reported to Model Human Disease (Disease Ontology) (15 alleles)

Not1

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

Not1^GD4070

model of heart disease

CEA

(Elmén et al., 2020)

model of Vissers-Bodmer syndrome