Scientists uncover new genetic mutations linked to autism spectrum disorder

Scientists at Sanford Burnham Prebys Medical Discovery Institute and Radboud University Medical Center in the Netherlands have identified mutations in a gene called CNOT1 that affect brain development and impair memory and learning. The study is the first to link neurodevelopmental delays with CNOT1, suggesting that drugs that help restore the gene's function may have therapeutic benefit. The research, published in The American Journal of Human Genetics, also revealed that CNOT1 interacts with several known autism spectrum disorder (ASD) genes, opening new research avenues for the condition.

"Prior to this work, the CNOT1 gene was not on the radar of autism researchers," says Rolf Bodmer, Ph.D., director and professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys and the study's co-corresponding and co-senior author. "This discovery could help us better understand the genetic mechanisms underlying ASD. Our work is also a first step toward exploring drugs that could augment the function of CNOT1 and might be able to help children with neurodevelopmental delays who have these specific mutations."

The cause of developmental disabilities, including ASD, is poorly understood. Research indicates that there may be a genetic component to these conditions, but the precise impact of the genetic variations that have been uncovered to date is unclear. Identifying the underlying cause of developmental disabilities would allow scientists to create diagnostic tests that would provide early diagnoses and potential treatments.

A common genetic thread

In the current study, scientists at Radboud University Medical Center identified a commonality between 39 people with a neurological disorder: variations in the CNOT1 gene. These individuals, whose ages ranged from newborn to 22 years old, had symptoms that spanned from severe intellectual disability to nearly normal IQ and everyday functioning. The researchers hoped to determine if the variations in the CNOT1 gene were benign or the cause of the neurological symptoms--the first step to finding potential treatments.

To answer this question, the researchers at Radboud University turned to Bodmer, a world-renowned genetics expert who studies how genes contribute to disease using a fruit fly model. Sreehari Kalvakuri, Ph.D., a postdoctoral researcher in the Bodmer lab, created fruit flies that contained the same CNOT1 variations seen in the patients, including DNA sequences that were "misspelled" (missense), cut short (truncated) or otherwise altered.

This work identified nine CNOT1 variants that impaired learning and memory, which was measured by several independent approaches--including a courtship assay that tested the ability of male fruit flies to remember if their female partners had paired with other males. All of these variants appeared spontaneously (de novo) in the patients, meaning they were not inherited. The scientists also discovered that these CNOT1 mutations interact with known ASD genes--revealing a genetic link to ASD that can be further explored.

"Fruit flies are a great biological model because we can complete genetic studies very quickly. This work only took a few months instead of the potential decade using a mouse model," says Kalvakuri, the study's co-first author. "Additionally, the CNOT1 gene is highly conserved between fruit flies and humans, meaning it does not change much, so we are optimistic these findings can be extrapolated to people."

Next, the scientists plan to identify which molecular components interact with CNOT1, which functions as a scaffold that builds up a larger protein complex. This work might uncover additional potential drug targets for intellectual, learning or memory disorders, including ASD.

"The first step toward helping children with neurodevelopmental delays is to determine the cause of the condition," says Bodmer. "Our ultimate hope is to find a treatment that could be given as early as possible to help these children stay on track developmentally."

Surprisingly, the findings also have implications for heart disease, the primary focus of Bodmer's lab.

"A significant fraction of these patients also have cardiac defects," says Bodmer. "Conversely, children who are born with heart defects are at a higher risk of developing ASD, too. This study on CNOT1 also provides a previously unknown genetic link between heart function and ASD."

Developmental disabilities are a group of conditions characterized by impairments in physical, learning, language or behavioral areas. About one in six children in the U.S. have one or more developmental disabilities or other developmental delays, according to the Centers for Disease Control and Prevention.

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The study's DOI is 10.1016/j.ajhg.2020.05.017.

Research reported in this press release was supported by the Dutch Research Council (015.014.066), Cambridge Biomedical Centre and European Union (779257).

The co-senior authors of the study are Bodmer of Sanford Burnham Prebys and Arjan P.M. de Brouwer of Radboud University Medical Center. The co-first authors of the study are Kalvakuri of Sanford Burnham Prebys and Lisenka Vissers of Radboud University Medical Center.

Additional study authors include Elke de Boer, Sinje Geuer, Machteld Oud, Inge van Outersterp, Michael Kwint, Melde Witmond, Simone Kersten, Dilys Weijers, Hans van Bokhoven and Tjitske Kleefstra of Radboud University Medical Center; Daniel L. Polla of Radboud University Medical Center and CAPES Foundation in Brazil; Amber Begtrup, Kirsty McWalter and Megan T. Cho of GeneDx; Anna Ruiz and Elisabeth Gabau of Universitat Autònoma de Barcelona; Jenny E.V. Morton of Birmingham Women's and Children's NHS Foundation Trust; Christopher Griffith of the University of South Florida; Karin Weiss and Maximilian Muenke of Technion - Israel Institute of Technology; Candace Gamble of Cook Children's; James Bartley of Loma Linda University; Hilary J. Vernon of Johns Hopkins University School of Medicine; Kendra Brunet of Porcupine Health Unit; Claudia Ruivenkamp and Sarina G. Kant of Leiden University Medical Centre; Paul Kruszka of the National Institutes of Health; Austin Larson of the University of Colorado School of Medicine; Alexandra Afenjar of Sorbonne Université; Thierry Billette de Villemeur and Kimberly Nugent of Children's Hospital of San Antonio; the DDD Study of Wellcome Trust Sanger Institute; F. Lucy Raymond of the University of Cambridge; Hanka Venselaar of Radboud Institute for Molecular Life Sciences; Florence Demurger of Centre Hospitalier Bretagne Atlantique; Claudia Soler-Alfonso of Baylor College of Medicine; Dong Li and Elizabeth Bhoj of the Children's Hospital of Philadelphia; Ian Hayes of Genetic Health Service New Zealand; Nina Powell Hamilton, Ayesha Ahmad and Rachel Fisher of the University of Michigan; Myrthe van den Born of Erasmus MC; Marjolaine Willems of Centre Hospitalier Universitaire de Montpellier; Arthur Sorlin and Julian Delanne of Burgundy University and Dijon University Hospital; Sebastien Moutton of Burgundy University and Maison de Santé Protestante Bordeaux Bagatelle; Philippe Christophe, Frederic Tran Mau-Them and Antonio Vitobello of Burgundy University and Plateau Technique de Biologie; Himanshu Goel of the University of Newcastle; Lauren Massingham, Chanika Phornphutkul and Jennifer Schwab of the Warren Alpert Medical School of Brown University; Boris Keren and Perrine Charles of Pitié-Salpêtrière Hospital; Maaike Vreeburg of Maastricht UMC+; Lenika De Simone and George Hoganson of UIC Pediatric Genetics; Maria Iascone of ASST Papa Giovanni XXIII; Donatella Milani of Fondazione IRCCS; Lucie Evenepoel and Nicole Revencu of Université Catholique de Louvain; D. Isum Ward and Kaitlyn Burns of Sanford Health; and Ian Krantz, Sarah E. Raible, Jill R. Murrell and Kathleen Wood of the Children's Hospital of Philadelphia.

About Sanford Burnham Prebys Medical Research Institute

Sanford Burnham Prebys is a preeminent, independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 40 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children's diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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