Mutated Genes Were Never Associated With Zika

Patients with rare genetic mutations are helping scientists understand exactly how the Zika virus harms the developing brains of a fetus.

Researchers have uncovered one way that the Zika virus leads to microcephaly, a congenital condition resulting in smaller-than-normal head size and related mental developmental delays.

Congenital Zika syndrome is a unique pattern of birth defects and disabilities found among fetuses infected with the Zika virus during pregnancy.

A 2017 study in Brazil found that at 19-24 months of age, babies with congenital Zika virus infection exhibited challenges with sitting independently, feeding, and sleeping. 

Published in the Developmental Cell journal on November 14, 2019, this new research identifies a set of genes involved in microcephaly. 

And, one of these genes codes for a protein that’s targeted during Zika virus infection.

These researchers reported 6 additional patients with microcephaly that carry mutations in ANKLE2 and show that 3 variants identified in probands cause a loss of ANKLE2 function when tested in flies.

This information provides compelling evidence that its loss causes reduced brain size in flies and severe microcephaly (Z score < −2.5) in humans.

In the future, a drug that protects this protein could stop Zika’s damaging developmental effects, says study co-author Hugo J. Bellen, Ph.D., a Howard Hughes Medical Institute (HHMI) Investigator at Baylor College of Medicine, located in Houston, Texas.

“What’s interesting is that this set of genes was known in flies for more than 15 years and was never associated with microcephaly,” said Dr. Bellen

The Zika virus is transmitted by mosquitoes and, in healthy adults, generally causes mild symptoms. But when pregnant women are infected, the virus can have lifelong consequences for the fetus, including developmental abnormalities like microcephaly. 

Zika, previously a rare disease, became an international concern during a large outbreak that began in 2015.

Dr. Bellen and his colleagues didn’t set out to study Zika. 

But, in the course of a larger project, his team noticed that flies with a mutation in a gene called Ankle2 ended up with smaller-than-usual brains – a Drosophila manifestation of microcephaly. 

Then, in a database of patients with rare genetic mutations, they found patients with Ankle2 mutations who had severe cases of microcephaly from unknown causes. 

That was a sign that Ankle2 mutations might be relevant in human diseases that affect brain development, says study coauthor Nichole Link, Ph.D., a geneticist and developmental biologist in Dr. Bellen’s lab.

To figure out how Ankle2 mutations were influencing brain formation, the researchers went back to flies. 

Normally, Ankle2 works with a series of other genes to control the division of neuroblasts, stem cells that give rise to neurons. 

These cells are crucial for proper brain development. 

Mutations in the Ankle2 gene messed with the neuroblast division. Larval flies with the mutation had fewer neuroblasts and smaller-than-expected brains.

During 2018, Dr. Bellen’s team, working with Nevan Krogan’s team at the University of California, San Francisco, identified a protein produced during Zika virus infection that blocks the proper activity of the Ankle2 protein. 

In this project, the researchers have shown in more detail how that interaction harms brain development – by preventing neuroblasts from dividing correctly.

The find is part of a bigger initiative between Bellen’s lab and other scientists at Baylor and beyond, in which researchers use flies to study mutations found in patients with undiagnosed diseases. 

Hence, lessons learned from this study of rare diseases can provide insights into more common diseases and potential gene-environment interactions. This new work can help scientists learn more about an individual mutation’s functional effects.

Zika Developments published by Zika News