California [US], November 28 : An international research team led by Children's Hospital of Philadelphia (CHOP) experts has discovered how three unique genes cause neurodevelopmental problems.
Researchers now have a greater understanding of the genes' involvement in human brain development and function, as well as their potential to act as therapeutic targets in the future. The Journal of Clinical Investigation just published the findings online.
In the last few decades, researchers have discovered around 1500 genes in various signalling pathways linked to neurodevelopmental diseases. A genetic diagnosis is given to roughly one-third of patients with neurodevelopmental problems.
However, little is known about how these genes are linked together and how their malfunction results in various diseases.
Previous research on other illnesses has suggested that gene-splicing abnormalities may be to blame. Genes are transcribed into introns, or strands of RNA that do not code for proteins, and exons, which do code for proteins, before they are translated into proteins.
Introns are removed in a process called splicing, which is carried out by a protein complex called the spliceosome.
Variants impacting the spliceosome have rarely been implicated in neurodevelopmental disorders. However, through a series of complex tests, researchers in this study showed that malfunctions in the spliceosome are responsible for some neurodevelopmental disorders.
"Using multiple techniques, including phenotyping, genomic sequencing and modelling in fly and stem cells, we were able to map the genetic architecture of three genes associated with neurodevelopmental disorders, particularly developmental delay, intellectual disability and autism," said Dong Li, PhD, a research faculty member in the Center for Applied Genomics and the Division of Human Genetics at CHOP and lead author on the study.
"Combining fly and human genetics helped us understand the mechanisms of how variants of these genes affect the machinery of the spliceosome and cause these disorders."
In this study, researchers utilised genomic and clinical data from unrelated patients with neurodevelopmental disorders. Among the cohort, 46 patients had missense variants of the gene U2AF2 and six patients had variants of the gene PRPF19.
In human stem cell and fly models, the researchers noticed issues with the formation of neurites, or protrusions on neurons that give them their shape, as well as issues with splicing and social deficits in the fly models.
Deeper profiling revealed that the third gene, RBFOX1, had missense variants that affected splicing and loss of proper neuron function. These findings were later compared with those of patients in the study, which confirmed that variants in the three genes can lead to neurodevelopmental disorders.
"We used fruit flies to study the effects of losing the function of these three genes one at a time and found that two genes independently led to brain structural and functional abnormalities, highlighting the essentiality of these genes in development," said study co-author Yuanquan Song, PhD, an associate professor from the Department of Pathology & Laboratory Medicine at CHOP.
"Apart from identifying patients with such variants in these genes for the first time, our extended translational modelling study efforts aimed to determine the underlying functions for these variants, further elucidating their clinical relevance."
"Not only does this study identify three causative genes associated with neurodevelopmental disorders, but it helps us understand how critical pre-mRNA splicing is to the development of the central nervous system," said senior study author Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP.
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