Scientists uncover new genetic mutations linked to autism spectrum
disorder

Date:
June 24, 2020
Source:
Sanford Burnham Prebys Medical Discovery Institute
Summary:
Scientists have identified mutations in a gene called CNOT1 that
affect brain development and impair memory and learning. The
research also revealed that CNOT1 interacts with several known
autism spectrum disorder (ASD) genes, opening new research avenues
for the condition.



FULL STORY ========================================================================== 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.


========================================================================== Story Source: Materials provided by Sanford_Burnham_Prebys_Medical_Discovery_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Lisenka E.L.M. Vissers, Sreehari Kalvakuri, Elke de Boer, Sinje
Geuer,
Machteld Oud, Inge van Outersterp, Michael Kwint, Melde Witmond,
Simone Kersten, Daniel L. Polla, Dilys Weijers, Amber Begtrup,
Kirsty McWalter, Anna Ruiz, Elisabeth Gabau, Jenny E.V. Morton,
Christopher Griffith, Karin Weiss, Candace Gamble, James Bartley,
Hilary J. Vernon, Kendra Brunet, Claudia Ruivenkamp, Sarina G. Kant,
Paul Kruszka, Austin Larson, Alexandra Afenjar, Thierry Billette
de Villemeur, Kimberly Nugent, F.

Lucy Raymond, Hanka Venselaar, Florence Demurger, Claudia
Soler-Alfonso, Dong Li, Elizabeth Bhoj, Ian Hayes, Nina Powell
Hamilton, Ayesha Ahmad, Rachel Fisher, Myrthe van den Born,
Marjolaine Willems, Arthur Sorlin, Julian Delanne, Sebastien
Moutton, Philippe Christophe, Frederic Tran Mau-Them, Antonio
Vitobello, Himanshu Goel, Lauren Massingham, Chanika Phornphutkul,
Jennifer Schwab, Boris Keren, Perrine Charles, Maaike Vreeburg,
Lenika De Simone, George Hoganson, Maria Iascone, Donatella
Milani, Lucie Evenepoel, Nicole Revencu, D. Isum Ward, Kaitlyn
Burns, Ian Krantz, Sarah E. Raible, Jill R. Murrell, Kathleen
Wood, Megan T. Cho, Hans van Bokhoven, Maximilian Muenke,
Tjitske Kleefstra, Rolf Bodmer, Arjan P.M. de Brouwer. 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. The American Journal of Human Genetics,
2020; DOI: 10.1016/j.ajhg.2020.05.017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200624082710.htm

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