Using zebrafish models, investigators have discovered that MAP4K4 genetic variants cause neurodevelopmental delays and other physical abnormalities, demonstrating a potential therapeutic target for treating the disorder in humans, according to findings published in Science Advances.
Zebrafish and humans share approximately 70 percent of the same genes, making zebrafish a useful model for studying developmental disorders and diseases in humans. Zebrafish also physiologically develop more quickly than other traditional laboratory animals, which can accelerate scientific investigation and discovery.
“The zebrafish genome is highly conserved to humans. There is very high similarity of the cellular processes that are involved in organ development, and they are also a highly tractable experimental model,” said Erica Davis, PhD, associate professor of Pediatrics, of Cell and Developmental Biology and a co-author of the study.
In previous clinical and genetics studies, Davis and collaborators identified 26 individuals from 21 unrelated families who displayed similar neurodevelopmental, cardiac and facial differences, and discovered that all of these affected individuals had a series of rare genetic variants in the MAP4K4 gene.
“At the time when we identified the first patient, MAP4K4 was not implicated in any human genetic condition. We did not know of anybody else in the world who had a rare DNA change in that gene associated with these clinical features,” Davis said.
To better understand the role of MAP4K4 and its genetic variants in early development, Davis and her team created zebrafish models of the patients’ clinical features by altering the function of the MAP4K4 gene in the zebrafish genomes.
Using advanced imaging to study the zebrafish cells and tissues as they developed, the investigators found that MAP4K4 genetic variants impaired protein function, and that inhibiting MAP4K4 activity caused developmental defects and abnormalities in the zebrafish organ systems.
They also found that MAP4K4 variants negatively regulate RAS signaling in the zebrafish during embryonic development, which inhibited proper cell survival, growth and differentiation.
“MAP4K4 is a known component of the RAS signaling pathway and hyperactivity in this pathway has been characterized in several types of cancer,” according to Davis.
The current findings establish MAP4K4 as the cause of RAS signaling deficits in the embryo and suggest it may be an effective therapeutic target in treating neurodevelopmental disorders in humans. Davis added that having MAP4K4 added to clinical diagnostic testing will also help expecting families better prepare for acquiring additional support and care.
“This study adds another gene to the known set of genes that causes a rare developmental syndrome… and to have that genetic diagnosis is really, really powerful for parents,” Davis said.
This work was partially supported by the National Center for Advancing Translational Sciences grant R21TR002770, National Institute of Child Health and Development R01HD105868 and the National Institute of Mental Health grant R01MH106826.
