TY - JOUR
T1 - 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
AU - The DDD Study
AU - Vissers, Lisenka E.L.M.
AU - Kalvakuri, Sreehari
AU - de Boer, Elke
AU - Geuer, Sinje
AU - Oud, Machteld
AU - van Outersterp, Inge
AU - Kwint, Michael
AU - Witmond, Melde
AU - Kersten, Simone
AU - Polla, Daniel L.
AU - Weijers, Dilys
AU - Begtrup, Amber
AU - McWalter, Kirsty
AU - Ruiz, Anna
AU - Gabau, Elisabeth
AU - Morton, Jenny E.V.
AU - Griffith, Christopher
AU - Weiss, Karin
AU - Gamble, Candace
AU - Bartley, James
AU - Vernon, Hilary J.
AU - Brunet, Kendra
AU - Ruivenkamp, Claudia
AU - Kant, Sarina G.
AU - Kruszka, Paul
AU - Larson, Austin
AU - Afenjar, Alexandra
AU - Billette de Villemeur, Thierry
AU - Nugent, Kimberly
AU - Raymond, F. Lucy
AU - Venselaar, Hanka
AU - Demurger, Florence
AU - Soler-Alfonso, Claudia
AU - Li, Dong
AU - Bhoj, Elizabeth
AU - Hayes, Ian
AU - Hamilton, Nina Powell
AU - Ahmad, Ayesha
AU - Fisher, Rachel
AU - van den Born, Myrthe
AU - Willems, Marjolaine
AU - Sorlin, Arthur
AU - Delanne, Julian
AU - Moutton, Sebastien
AU - Christophe, Philippe
AU - Mau-Them, Frederic Tran
AU - Vitobello, Antonio
AU - Goel, Himanshu
AU - Massingham, Lauren
AU - Milani, Donatella
PY - 2020/7/2
Y1 - 2020/7/2
N2 - 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.
AB - 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.
KW - CCR4-NOT complex
KW - CNOT1
KW - de novo mutations
KW - developmental delay
KW - Drosophila
KW - exome sequencing
KW - genomics
KW - intellectual disability
KW - neurodevelopment
UR - http://www.scopus.com/inward/record.url?scp=85087017130&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087017130&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.05.017
DO - 10.1016/j.ajhg.2020.05.017
M3 - Article
AN - SCOPUS:85087017130
VL - 107
SP - 164
EP - 172
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -