Why mutations that would seemingly affect all cells lead to face-specific birth defects

January 25, 2018, Massachusetts Institute of Technology
Researchers have discovered how mutations in genes required for basic cellular functions give rise to face-specific birth defects. Credit: Chelsea Turner/MIT

About 1 in 750 babies born in the United States has some kind of craniofacial malformation, accounting for about one-third of all birth defects.

Many of these craniofacial disorders arise from of "housekeeping" genes, so called because they are required for basic functions such as building proteins or copying DNA. All cells in the body require these housekeeping genes, so scientists have long wondered why these mutations would produce defects specifically in facial tissues.

Researchers at MIT and Stanford University have now discovered how one such mutation leads to the facial malformations seen in Treacher-Collins Syndrome, a disorder that affects between 1 in 25,000 and 1 in 50,000 babies and produces underdeveloped facial bones, especially in the jaw and cheek.

The team found that that form the face are more sensitive to the mutation because they more readily activate a pathway that induces in response to stress. This pathway is mediated by a protein called p53. The new findings mark the first time that scientists have determined how mutations in can have tissue-specific effects during embryonic development.

"We were able to narrow down, at the molecular level, how issues with general regulators that are used to make ribosomes in all cells lead to defects in specific cell types," says Eliezer Calo, an MIT assistant professor of biology and the lead author of the study.

Joanna Wysocka, a professor of chemical and systems biology at Stanford University, is the senior author of the study, which appears in the Jan. 24 online edition of Nature.

From mutation to disease

Treacher-Collins Syndrome is caused by mutations in genes that code for proteins required for the assembly and function of polymerases. These proteins, known as TCOF1, POLR1C, and POLR1D, are responsible for transcribing genes that make up cell organelles called ribosomes. Ribosomes are critical to all cells.

"The question we were trying to understand is, how is it that when all cells in the body need ribosomes to function, mutations in components that are required for making the ribosomes lead to craniofacial disorders? In these conditions, you would expect that all the cell types of the body would be equally affected, but that's not the case," Calo says.

During embryonic development, these mutations specifically affect a type of embryonic cells known as cranial neural crest cells, which form the face. The researchers already knew that the mutations disrupt the formation of ribosomes, but they didn't know exactly how this happens. To investigate that process, the researchers engineered larvae of zebrafish and of an aquatic frog known as Xenopus to express proteins harboring those mutations.

Their experiments revealed that the mutations lead to impairment in the function of an enzyme called DDX21. When DDX21 dissociates from DNA, the genes that encode ribosomal proteins do not get transcribed, so ribosomes are missing key components and can't function normally. However, this DDX21 loss only appears to happen in cells that are highly sensitive to p53 activation, including cranial neural crest cells. These cells then undergo programmed cell death, which leads to the seen in Treacher-Collins Syndrome, Calo says.

Other embryonic cells, including other types of neural crest cells, which form nerves and other parts of the body such as connective tissue, are not affected by the loss of DDX21.

Role of DNA damage

The researchers also found that mutations of POLR1C and POLR1D also cause damage to stretches of DNA that encode some of the RNA molecules that make up ribosomes. The amount of DNA damage correlated closely with the severity of malformations seen in individual larvae, and mutations in POLR1C led to far more DNA damage than mutations in POLR1D. The researchers believe these differences in DNA damage may explain why the severity of Treacher-Collins Syndrome can vary widely among individuals.

Calo's lab is now studying why affected cells experience greater levels of DNA damage in those particular sequences. The researchers are also looking for compounds that could potentially prevent craniofacial defects by making the cranial neural crest more resistant to p53-induced cell death. Such interventions could have a big impact but would have to be targeted very early in , as the cranial begin forming the tissue layers that will become the face at about three weeks of development in human embryos.

Explore further: Similarities unite three distinct gene mutations of Treacher Collins syndrome

More information: Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders Nature, DOI: 10.1038/nature25449 , https://www.nature.com/articles/nature25449

Related Stories

Similarities unite three distinct gene mutations of Treacher Collins syndrome

July 22, 2016
Scientists at the Stowers Institute for Medical Research have reported a detailed description of how function-impairing mutations in polr1c and polr1d genes cause Treacher Collins syndrome (TCS), a rare congenital craniofacial ...

Scientists transform lower-body cells into facial cartilage

June 27, 2016
Caltech scientists have converted cells of the lower-body region into facial tissue that makes cartilage, in new experiments using bird embryos. The researchers discovered a "gene circuit," composed of just three genes, that ...

Vaping while pregnant could cause craniofacial birth defects, study shows

November 16, 2017
Using e-cigarettes during pregnancy could cause birth defects of the oral cavity and face, according to a recent Virginia Commonwealth University study.

Scientists ID key fetal cells vulnerable to Zika

September 29, 2016
(HealthDay)—The devastating mosquito-borne Zika virus can infect cells that play a role in skull development, a new study finds.

Epigenetic regulation of face formation

March 30, 2017
Each face is unique, even though the genes controlling facial shape are almost identical in every individual. Filippo Rijli and his team at the Friedrich Miescher Institute for Biomedical Research (FMI) have discovered an ...

Recommended for you

Identifying Crohn's disease risk factors in the Ashkenazi Jewish population

May 25, 2018
It is estimated that one in three individuals of Ashkenazi Jewish (AJ) descent carry mutations that increase their risk for certain genetic diseases. For instance, Crohn's, a highly heritable inflammatory bowel disease, is ...

How do insects survive on a sugary diet?

May 25, 2018
There's a reason parents tell their kids to lay off the sugar: too much isn't good for you.

Regulatory mutations missed in standard genetic screening lead to congenital diseases

May 25, 2018
Researchers have identified a type of genetic aberration to be the cause of certain neurodevelopmental disorders and congenital diseases, such as autism and congenital heart disease, which are undetectable by conventional ...

New chromosome study can lead to personalised counselling of pregnant women

May 25, 2018
Foetuses with a so-called new balanced chromosomal aberration have a higher risk of developing brain disorders such as autism and mental retardation than previously anticipated. The risk is 20 per cent for foetuses with these ...

New findings on autism-related disorder

May 24, 2018
In a study published today in Nature, Marc Bühler and his group at the Friedrich Miescher Institute for Biomedical Research (FMI) have taken a major step forward in elucidating the mechanisms underlying a disorder known ...

Genome study presents new way to track historical demographics of US populations

May 24, 2018
Sharon Browning of the University of Washington and colleagues developed a method to estimate historical effective population size, which is the number of individuals who pass on their genes to the next generation, to reveal ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.