Researchers studying the genetic origins of neurodevelopmental disorders have picked apart the pathways that underlie an incredibly rare congenital syndrome, a finding which the authors hope can be applied to related conditions such as autism spectrum disorder (ASD).
Neurodevelopmental disorders often result from genetic mutations and present an ongoing challenge for the medical field. Despite decades of research efforts and advances in genetic technologies, a critical issue remains; it is extremely difficult to safely and effectively interfere with an individual’s genetic make-up. Thus, the development of effective therapies will depend on a solid understanding of the biological and molecular pathways underpinning the condition.
Kaufman oculocerebrofacial syndrome (KOS) is an autosomal recessive congenital disorder. KOS has affected only a handful of people since it was first described in 1971. Children receiving a KOS diagnosis typically present with prenatal-onset microcephaly, hypotonia, short stature, eye abnormalities, intellectual disability and lack of speech. Based on these symptoms it is likened to ASD.
The Challenge for Neurodevelopmental Disorder Research
Dr Maria Chahrour, a neurogeneticist at the University of Texas Southwestern Medical Centre, is leading several projects to identify disease-causing mutations and study the pathways that are involved in. In their most recent work, published in Proceedings of the National Academy of Sciences, Chahrour’s team utilized a mouse model to study the impact of UBE3B and BCKDK gene knock out on the animal’s physiology.
“We have known for decades that genetic factors contribute to autism spectrum disorder (ASD), and in recent years hundreds of genes have been linked to the condition. The challenge now is to determine the contribution of each of these genetic causes to the patient population, and more importantly, the different molecular mechanisms involved in the etiology of ASD,” says Chahrour. “We are excited about this finding in KOS because it represents an initial step towards understanding the underlying biological pathways that are affected.”
Their findings illustrate that the absence of UBE3B leads to KOS. The UBE3B protein is an E3 ubiquitin ligase, which functions as part of the ubiquitin-proteasome system which cells use to breakdown unwanted proteins. Whilst the role of UBE3B absence in KOS was already known, the precise mechanisms by which the lack of UBE3B protein in the brain causes the symptoms observed in KOS remained elusive.
The results from the animal model also showed that a second protein, BCKDK, accumulates in the brain in the absence of UBE3B. The BCKDK protein’s molecular function is to catalzye the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, and defects in the BCKDK gene are associated with ASD.
“There are few neurodevelopmental disorders associated with autism where we have some understanding of the molecular mechanisms involved. Very few ASD genes have been studied in depth and so we are excited about this finding in KOS because it represents an initial step towards understanding the underlying biological pathways that are affected.” Whilst Chahrour herself admits that no animal model translates perfectly to humans, she points out that all the phenotypes noted in the mouse model are also seen in KOS patients. The model showed similar metabolite changes to those seen in KOS patients.
Chahrour thinks that the platform should be able useful for testing different approaches aimed at potentially rescuing the KOS phenotype.
Looking to the future of the field, Chahrour hopes that genetic tests will soon form the basis of a diagnostic platform for ASD: “A challenge with genetic testing is that for the majority of cases these tests come back negative because we still don’t know all the genetic causes of ASD. However, with all the large-scale genomics projects underway worldwide, we are hopeful that a more comprehensive understanding of ASD genetics will lead to better genetic tests.” Such innovations will not only forward research but will provide valuable information to patients and their families. Chahrour concludes: “In addition to providing a diagnosis, genetic testing has the unique ability to answer the “why” that families seek; sometimes knowing the origin/cause of ASD can be gratifying. It can also help some families decide whether they want to have more children.”