Dataset Information

De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

ABSTRACT: CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.

SUBMITTER: Vissers LELM

PROVIDER: S-EPMC7332645 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Vissers Lisenka E L M LELM Kalvakuri Sreehari S de Boer Elke E Geuer Sinje S Oud Machteld M van Outersterp Inge I Kwint Michael M Witmond Melde M Kersten Simone S Polla Daniel L DL Weijers Dilys D Begtrup Amber A McWalter Kirsty K Ruiz Anna A Gabau Elisabeth E Morton Jenny E V JEV Griffith Christopher C Weiss Karin K Gamble Candace C Bartley James J Vernon Hilary J HJ Brunet Kendra K Ruivenkamp Claudia C Kant Sarina G SG Kruszka Paul P Larson Austin A Afenjar Alexandra A Billette de Villemeur Thierry T Nugent Kimberly K Raymond F Lucy FL Venselaar Hanka H Demurger Florence F Soler-Alfonso Claudia C Li Dong D Bhoj Elizabeth E Hayes Ian I Hamilton Nina Powell NP Ahmad Ayesha A Fisher Rachel R van den Born Myrthe M Willems Marjolaine M Sorlin Arthur A Delanne Julian J Moutton Sebastien S Christophe Philippe P Mau-Them Frederic Tran FT Vitobello Antonio A Goel Himanshu H Massingham Lauren L Phornphutkul Chanika C Schwab Jennifer J Keren Boris B Charles Perrine P Vreeburg Maaike M De Simone Lenika L Hoganson George G Iascone Maria M Milani Donatella D Evenepoel Lucie L Revencu Nicole N Ward D Isum DI Burns Kaitlyn K Krantz Ian I Raible Sarah E SE Murrell Jill R JR Wood Kathleen K Cho Megan T MT van Bokhoven Hans H Muenke Maximilian M Kleefstra Tjitske T Bodmer Rolf R de Brouwer Arjan P M APM

American journal of human genetics 20200617 1

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated v ...[more]

PMID: 32553196

Dataset Information

De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Publications

De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

De novo variants in ATP2B1 lead to neurodevelopmental delay.
| S-EPMC9118097 | biostudies-literature

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders.
| S-EPMC6612514 | biostudies-literature

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.
| S-EPMC8322935 | biostudies-literature

De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.
| S-EPMC5223060 | biostudies-literature

GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy.
| S-EPMC9606381 | biostudies-literature

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders.
| S-EPMC5846454 | biostudies-literature

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.
| S-EPMC6871531 | biostudies-literature

De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.
| S-EPMC5630160 | biostudies-literature

De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.
| S-EPMC7058825 | biostudies-literature

De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.
| S-EPMC6369454 | biostudies-literature