‘Autistic kids inherit mutated protein crucial for memory and learning’

Children with autism spectrum disorder (ASD) inherit from their parents an alteration in an enzyme/protein present in the brain which changes and affects certain cognitive abilities, finds a new India-led international collaborative study.

A nine-member team, led by the Bengaluru-based Institute for Stem Cell Science and Regenerative Medicine (inStem), has identified a novel mutation in the protein (p70 S6 Kinase 1 or S6K1) that occurs in some families with children diagnosed with ASD. This mutation in the protein, which is important for learning and memory as well as the functioning of the heart, pancreas and muscles, however does not impact the parents or unaffected siblings. Their study was published last week in the journal Neurobiology of Learning and Memory.

Globally, ASD is an important cause of developmental delay that can affect a baby, toddler or preschooler. The condition is characterised by poor social communication in terms of language, non-verbal signs of social interaction and compulsive interests that a child insists on engaging with to the exclusion of everything else. Mental retardation, epilepsy and attention deficit issues usually also accompany ASD.

Scientists at inStem, along with collaborators from the Center for Neural Science, New York University, and Cold Spring Harbor Laboratories, United States of America, focused on inherited mutations on autistic children for this study.

“We have long wondered whether subtle mutations can add up to change how severe the ASD symptoms can be in a child and this may directly determine how well they respond to therapy,” said Aditi Bhattacharya, corresponding author and independent investigator at the Center for NeuroSynaptopathy at inSTEM.

The team found the S6K1 mutation important for protein synthesis in the Simon Simplex Collection genetic database that has sequenced more than 2,700 families called simplex or quads, comprising DNA sequenced of both parents from families with only one child with ASD, or one normal developing child and one with ASD. The Simon Simplex Collection genetic database of the SFARI Foundation (https://gene.sfari.org/) is a resource of identification of genetic risk factors for autism.

“Timely protein synthesis is a key requirement for proper brain development and function as new proteins are made “on demand” when we encode a memory or learn a new skill,” said Bhattacharya.

Through a series of biochemical tests in two different kinds of cells, results uncovered how the mutant S6k1 enzyme was hyper active, which increased protein synthesis across the board and changed the function of developing neurons. The team also found that the mutant protein could not be targeted by small molecule drugs, which has important implications for a slew of drugs developed for S6k1 that are being prepared for clinical trials for other conditions as well. “The study showed that S6k1 mutation changed the course of normal neural development when expressed in stem cell line and also changed the structure of cultured neurons, which would likely also change its memory forming capacity,” said Bhattacharya. “The mutation’s presence is fairly common in the population and future steps would be to test how this altered S6k1 would change function of pancreatic, cardiac and skeletal muscle cells.”

Scientists not involved in the research said the study is the first to characterise the human S6K1 protein variant on cognitive functions.

“Until now, we did not know if the function of a particular variant of S6K1 exists in healthy condition. Studies have hinted on the critical role of S6K1 in learning and memory, and pharmacological inhibition of the same in a disease model ameliorated the symptoms,” said James Premadoss Clement, assistant professor, neuroscience unit, Jawaharlal Nehru Center for Advanced Scientific Research, Bengaluru, who was not involved in the study. “The authors have focused on understanding the impact of a particular variant, RPS6KB1, on learning and memory and other cognitive functions in normal as well as diseased conditions.”

In India, more than two million are estimated to be affected by ASD with a prevalence of 8.3 per 10,000 children, between the ages 3-12 years. Though the signs show up as early as six months, diagnosis in India usually takes place when the child is 3-5 years old, when most missed milestones of development are noticed. Researchers said this work is early evidence that inherited mutations in neurological conditions may be a good place to look for mapping variations in symptoms of diseases and responses to treatment.

“This study has demonstrated how excessive activity of S6K1 impacts neuronal development and function and further showed that S6K1 is a potential therapeutic target to treat ASD,” said Clement, whose expertise lies in autism and brain development.

Researchers who undertook the study said ASD is a very complex condition, but has been recognised to have a strong genetic basis worldwide. Studies have shown that as compared to normal children, those with ASD have more-than-usual disruptive mutations in their genetic material – genome – which may either be inherited from parents or can crop up only in autistic children. Over the last decade, research across the globe focused on unique mutations, while acknowledging inherited mutations from parents may have some effect, which is unclear. At the other end, scientists said the genetic bases for almost all diseases are being searched for following the release of the human genome 20 years ago.

“Two kinds of mutations have also been found. One causal, meaning just their presence can cause the disease. The other is an influencer mutation, which doesn’t cause the disease but changes response to medicines, severity of symptoms etc,” said Bhattacharya. “As a practice, causal mutations are studied, but influencer mutations have gained importance with the advent of precision medicine and biomarker development.”