The scientists have adapted a classic research technique called forward genetics to identify new genes involved in autism spectrum disorder (ASD). In a study published in eLife, the researchers used this approach in mice to find one such gene called KDM5A.
Approximately 1 in 54 children in the U.S. is diagnosed with ASD, a neurodevelopmental disorder that causes disrupted communication, difficulties with social skills, and repetitive behaviors. As a disease with a strong genetic component, it is hypothesized that thousands of genetic mutations may contribute to ASD. But to date, only about 30 percent of cases can be explained by known genetic mutations.
For decades, forward genetics has been used to find mutations that cause disease. It involves inducing genetic mutations in mice, screening for certain phenotypes, and then identifying the causative mutation through sequencing of all genetic material of an organism, or its genome.
"The difficult part in the beginning was finding the mutations. It had to be done by laborious cloning," says Nobel Laureate and study co-author. "We developed a platform wherein when you see a phenotype you know the mutational cause at the same time." So, when a mouse displays a certain phenotype or trait of interest, the researchers would know almost instantly what genetic mutation was causing it. This technique, combined with a screen developed to ascertain ASD-like behaviors in mice, made it possible to use forward genetics for the first time to identify new genetic mutations in ASD.
In this study, the research team documented the quality and number of vocalizations in young mice carrying induced genetic mutations. Given that one of the common characteristics seen in autism is disrupted communication, the researchers were on the lookout for mice that had changes in these vocalizations.
"Initially we found that the quality of these vocalizations was different in mice with KDM5A mutations. Looking more closely, we found that mice completely lacking KDM5A have a severe deficit in the number of these vocalizations," says the study lead.
In addition to loss of vocalizations, mice lacking KDM5A also displayed repetitive behaviors and deficits in social interaction, learning, and memory - all hallmarks of ASD.
Because this was the first time that KDM5A had been implicated in ASD, the researchers looked into whether KDM5A mutations could be found in patients with autism as well. Through international collaborative efforts, the group was able to identify nine patients with ASD and causative KDM5A mutations. Strikingly, eight out of nine patients also had a complete lack of speech.
Though one broad term is used for ASD, the lead author likens autism to cancer in that it is a collection of individually rare forms of autism with hundreds of different genetic causes. Mutations in KDM5A appear to be one of those forms.
"We've identified a new genetic subtype of autism, and we're going to look for more patients with mutations in KDM5A," explains the author. "This has a direct impact on diagnosis too. When a clinician gets a clinical sequencing result that reports a KDM5A mutation, it's now a known autism gene."
Aside from the impact on diagnosis, the researchers are interested in further characterizing this gene's role in the brain. With a better understanding of what KDM5A is doing in the brain, scientists might be able to find a target to aid in future studies investigating possible treatments.
This work will expand beyond KDM5A as researchers search for more genes involved in ASD, a subject of research for which the simplicity and efficiency of forward genetics comes in handy.
"The wonderful thing about forward genetics is that we can grind away at the genome. We know progressively how much of the genome we've saturated," says the senior author, who estimates that his group has already mutated about half of the mouse genome with this approach.
https://www.utsouthwestern.edu/newsroom/articles/year-2020/new-gene-autism-spectrum-disorder.html
https://elifesciences.org/articles/56883
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fkdm5a-mutations&filter=22
A new gene involved in autism spectrum disorder
- 1,320 views
- Added
Edited
Latest News
Protein that helps COVID-19…
By newseditor
Posted 26 Jul
Spinal Muscular Atrophy (SM…
By newseditor
Posted 26 Jul
Link between bowel movement…
By newseditor
Posted 26 Jul
Inhibition of IL-11 signall…
By newseditor
Posted 25 Jul
Brain changes linked to obe…
By newseditor
Posted 25 Jul
Other Top Stories
'Natural killer' cells could halt Parkinson's progression
Read more
How inflammation triggers fatal cycle in Alzheimer's disease
Read more
A protein controls inflammation through non-enzymatic activities
Read more
Sex-specific traits of the immune system explain men's susceptibili…
Read more
Too much salt weakens the immune system and may increase infections
Read more
Protocols
A systems biology approach…
By newseditor
Posted 24 Jul
quantms: a cloud-based pipe…
By newseditor
Posted 22 Jul
Emerging tools and best pra…
By newseditor
Posted 19 Jul
Directly selecting cell-typ…
By newseditor
Posted 17 Jul
PUFFFIN: an ultra-bright, c…
By newseditor
Posted 16 Jul
Publications
Hepatocyte-intrinsic SMN de…
By newseditor
Posted 26 Jul
Aberrant bowel movement fre…
By newseditor
Posted 26 Jul
A pseudoautosomal glycosyla…
By newseditor
Posted 26 Jul
Microglia protect against a…
By newseditor
Posted 26 Jul
Rigor and reproducibility i…
By newseditor
Posted 26 Jul
Presentations
Myelin plasticity in the ve…
By newseditor
Posted 10 Jun
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar