By Edwin L. Aguirre
Deformities of the head and facial bones, such as cleft lip or cleft palate, are among the most common and debilitating human birth defects, affecting about 1 in 500 births in developed countries. Children born with these craniofacial anomalies, or CFAs, often suffer from speech and dental problems and maybe at greater risk for learning, developmental or social challenges.
Diagnosing and treating CFAs is complicated by variation in the severity of the defects. Researchers widely recognize that genetic mutations can lead to the development of CFAs, but it is still unknown what mechanisms contribute to this variation.
Asst. Prof. Jennifer L. Fish of the Department of Biological Sciences is spearheading a project to understand the molecular mechanisms responsible in patients who have mutations in the gene called SATB2. Her research, which is funded by a three-year, $366,000 grant from the National Institutes of Health (NIH), will study how mutations in SATB2 cause defects, specifically in the growth of the lower jaw, and why these defects vary from individual to individual.
“These people, who suffer from a condition known as SATB2-associated syndrome, or SAS, often have cleft palates and small lower jaws, both of which are essentially defects in jaw growth during development of the fetus. In some patients the defects are more severe than in others, and we want to understand why that variation exists,” says Fish.
Fish is collaborating with Yuri Zarate, M.D., of the Arkansas Children’s Hospital in Little Rock, who treats patients with SAS.
“Last summer, Dr. Zarate organized a retreat for children with SAS and their families,” says Fish. “I attended to give a research update and talk to the families. The parents obviously care about potential treatments for their children, but it was also clear that it is really important to the families to understand what went wrong during their child’s development and to have some idea of what to expect going forward.”
Although Fish and Zarate’s research efforts will not lead to new diagnostic tools for the early detection of the deformities before a child is born (which can be done through genetic screening), it will help improve researchers’ understanding of how SATB2 is involved in jaw growth. “We can potentially help mediate progressive defects as the child ages and the jaw grows,” says Fish.
Fish points out that these individuals often suffer from lack of symmetry of the face, which her team hopes to prevent someday.
“Children with SAS also have low bone-mineral density in all of their bones, not just the jaw. Low bone-mineral density contributes to a high incidence of fractures in the long bones of SAS patients. Our work will also potentially help improve bone density in SAS patients and prevent bone fractures,” she says.
Understanding Disease-causing Genetic Mutations
In addition to the NIH-funded project, Fish is also a co-investigator on a related study headed by researchers from University of California San Francisco and the University of Calgary in Alberta, Canada, to understand how developmental systems in vertebrates can compensate for disease-causing genetic mutations.
“For example, most diseases are recessive – that is, mutations in both paternal and maternal genes need to be present for a birth defect to occur,” Fish explains.
“This means that development of the embryo typically proceeds normally even when a mutation is present in one copy of an important gene, but it’s not really known why that is the case. Our goal is to understand the reason behind this.”
Researchers do not know exactly how a specific mutation relates to developmental defects. “This is because development operates through the interaction of many genes, and some of these interactions may compensate for mutations. We want to understand how that compensation occurs,” says Fish, whose team’s findings were published online on Dec. 6 in the journal “Nature Communications.”
She adds that the same mutation can cause mild defects in one individual and severe defects in another. “This can happen even for two individuals within the same family. Why do disease-causing mutations cause so much variation in the severity of defects? Finding the answer to this question is a major goal of our research,” says Fish.