Clock Gene Mutation Contributes to The Development of Autism

by Rituparna Mishra

Autism is a neurodevelopmental disorder which is characterized by challenges with social interaction, behavioral patterns, speech and communication abilities. In 2013, the American Psychiatric Association changed this term to autism spectrum disorder (ASD) which covers conditions inclusive of autistic disorder, pervasive developmental disorder and asperger syndrome. ASD is known to affect 1 in every 44 children in the U.S according to the Centers for Disease Control and Prevention.

Recently, a study conducted at the University of Minnesota Medicine School revealed that circadian rhythm sleep disorder can be noticed in those with ASD. Around 50-80% of children suffering from ASD have sleep problems in comparison to around 30% of the general population. Our sleep cycle is controlled by the body’s biological ‘clock’ which regulates the circadian rhythm and sleep homeostasis. The biological clock is responsible for various functions ranging from hormonal regulation to the sleep-wake cycle. Circadian rhythms function based on the physical, emotional and behavioral changes that follow a 24-hour cycle.This includes response towards changes in light in the environment, which aids in the regulation of our sleep-wake cycles.

In current world situations, the sleep-wake cycle is usually disrupted due to work shifts. Other factors contributing to the disruption of the circadian rhythms include any mutations in certain genes, specific to the biological clock and changes in the light-dark cycle. However, according to Ruifeng Cao, an assistant professor of neuroscience at the University of Minnesota Medicine School, Duluth Campus and co-author of the study, "It has long been recognized that the function of the body clock is frequently disrupted in autism patients and these patients often exhibit various sleep problems.” Although, no direct relation between the clock gene disruption and development of autism has been found, it is suspected that it is one of the contributing factors.

On further analysis, it was found through preclinical trials that the disruption of an essential clock gene - the Bmal1 gene - contributes to the development of autistic-like phenotypes. The study revealed that the global or cerebellar erasure of the Bmal1 gene can cause repetitive behavioral patterns and challenges in social interactions such as communication. The Bmal1 gene is one of the key elements in the mammalian auto-regulatory transcription-translation negative feedback loop (TTFL) which generates molecular circadian rhythms. In the absence of this gene, the 24-hour activity pattern is lost or disrupted, and therefore, it allows many complications to rise. This is one of the main causes of the development of autism.

Alongside the abolished 24-hour cycle, the preclinical trials revealed that a disruption in the circadian rhythm could cause damage to the cerebellum leading to cerebellar ataxia. Ataxia occurs as a result of many diseases that cause loss of muscle control or loss of coordination of voluntary movements. This can indirectly affect many other movements and lead to inability or difficulty in speech, eye movement and swallowing. Upon further investigation, it was found that this damage to the cerebellum lead to various cellular and molecular changes, which indicates neurodevelopmental loss.

Lab principal investigator in neurobiology at Biomedical Research Institute (BRI) of the Foundation for Research and Technology Hellas (FORTH) in Greece, Christos Gkogkas claims that “Clock gene disruption could be a mechanism underlying several forms of autism and potentially other neurodevelopmental conditions, and this finding paves the way for further exciting research”. The research team consisting of scientists from the University of Minnesota Medicine School, University of Texas Health San Antonio, and the Biomedical Research Institute (BRI) of the Foundation for Research and Technology Hellas (FORTH) in Greece intend to continue their exploration of other genes responsible for generating molecular circadian rhythms and their link to ASD and other possible neurodevelopmental conditions.

Sources:

• https://my.clevelandclinic.org/health/diseases/8855-autism#:~:text=What%20is%20the%20difference%20between,Autistic%20disorder.
• https://www.autismspeaks.org/what-autism#:~:text=Autism%2C%20or%20autism%20spectrum%20disorder,in%20the%20United%20States%20today.
• https://www.sciencedaily.com/releases/2022/03/220324104544.htm
• https://www.sciencedaily.com/terms/circadian_rhythm_sleep_disorder.htm
• https://www.nigms.nih.gov/education/fact-sheets/Pages/circadian-rhythms.aspx#:~:text=Circadian%20rhythms%20are%20physical%2C%20mental,the%20study%20of%20circadian%20rhythms.
• https://pubmed.ncbi.nlm.nih.gov/32054765/
• https://www.mayoclinic.org/diseases-conditions/ataxia/symptoms-causes/syc-20355652