Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene offers new lead in cleft lip and palate research

25.09.2006
Researchers supported by the National Institutes of Health report in the current issue of the journal Science that a much-studied gene called SUMO1, when under expressed, can cause cleft lip and palate, one of the world's most common birth defects.

With several genes already implicated in causing cleft lip and palate, the authors note their addition to the list comes with a unique biological twist. The SUMO1 gene encodes a small protein that is attached to the protein products of at least three previously discovered "clefting" genes during facial development, in essence linking them into or near a shared regulatory pathway and now hotspot for clefting.

"The big challenge for research on cleft lip and palate is to move from studying individual genes to defining individual protein networks," said Dr. Richard Maas, a scientist at Brigham and Women's Hospital and Harvard University Medical School in Cambridge, Mass. and senior author on the paper. His research is supported by NIH's National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS).

"By protein network, I mean a nexus of proteins that interact in a highly regulated way," he continued. "It's at this dynamic, real-time level that science will begin to see the big picture and tease out more of the needed insights to understand and hopefully eventually prevent cleft lip and palate in newborns. What's exciting about SUMO1 is it allows us for the first time to begin to connect at least some of the dots and hopefully lock into a highly informative protein network that feeds into additional protein networks to form the palate, or roof of the mouth."

According to Maas, their discovery also offers a prime example of the power of genomic research, the comparative study of individual or sets of related genes among species, from yeast to human. The discovery also highlights the utility of comprehensive gene databases, DNA libraries, and other publicly accessible genomic resources to accelerate the pace of modern science.

Maas said the work that led to this weeks's Science paper began several months ago when a clinician sent a blood sample from a five-year-old patient who had been born with a cleft lip and palate but no other obvious abnormalities. The sample arrived as part of an international program in which Maas's lab participates, called the Developmental Genome Project, or DGAP.

Launched in the late 1990s, the NIGMS-supported project relies on clinicians to send to DGAP-affiliated laboratories DNA samples from consenting patients with birth defects that appear to be caused by chromosome rearrangement, particularly so-called "balanced translocations." A balanced translocation means that during the normal cell cycle, two chromosomes stick together, break, and form again incorrectly with parts of each chromosome switching places.

"DGAP builds on the hypothesis that the translocation splits a gene involved in the developmental process, renders it non functional, and causes a visible birth defect," said Dr. Fowan Alkuraya, a post-doctoral fellow in Maas's laboratory and co-lead author on the study. "In theory, the translocation will lead us to a biologically informative gene. The challenge is to prove that theory and reality are one and the same."

As the first step in the process, Alkuraya and colleagues found that the split gene in the patient's DNA sample encoded SUMO1, a small protein that is known to attach to the back of newly formed proteins to modify their function. "This was intriguing news because SUMO1 often attaches to, or tags, proteins to undergo a biochemical process called sumoylation, which influences their behavior," said Maas. "At least three of the previously identified clefting genes are known to be sumoylated and, if SUMO1 turned out to be involved in clefting, it might lead us to a relevant protein network."

To determine whether SUMO1 was indeed a clefting gene, the Maas lab turned to their experimental model of choice, the mouse. After establishing that SUMO1 is expressed in the region of the developing mouse where the palate forms, the scientists asked the next logical question: What happens if SUMO1 is expressed at abnormally low levels as the palate forms?

The scientists turned to a research consortium called BayGenomics that employs so-called "knockout," or gene inactivation, technology to for the systematic study of the individual genes with the mouse genome to decipher their possible functions. The consortium, supported by NIH's National Heart, Lung, and Blood Institute (NHLBI), has assembled a repository of embryonic stem cells for research purposes in which each available line has a different gene knocked out, or inactivated.

The Maas lab ordered the stem cell line in which SUMO1 had been partially inactivated, implanted them into female mice, and waited. The result: Four of 46 newborn mice had clefts of the palate or face. "That's about the incidence that we see in human families with a history of cleft lip and palate," said Dr. Irfan Saadi, a co-lead author on the study and post-doctoral fellow in the Maas lab. "So we weren't put off by the low incidence at all. It's what we would have expected."

In additional work, the scientists found that when SUMO1 and the sumoylated clefting gene Eya1 were both inactivated, clefting increased to 36 percent of newborn mouse pups, an indication that their proteins interact during palate development and a point that additional experiments further confirmed.

"Ten years ago, this work might have taken our laboratory years to perform," said Maas. "But with the genomic resources that are now readily available, we can get answers in a matter of weeks or months and, just as importantly, we spend a greater proportion of our time thinking through the biology rather than worrying why an assay isn't working."

With more tools and data to sift through, Maas noted that the long held distinctions between syndromic and non-syndromic cleft lip and palate have begun to blur. Traditionally, "syndromic" means babies are born with cleft lip and/or palate, in addition to other birth defects. "Non-syndromic" refers newborns who have cleft lip and/or palate only.

"Clefting reflects the combined actions of multiple gene products, rarely only one gene and its protein," said Maas. "That's why it's likely that what we now call non-syndromic has a very heterogenous mixture of manifestations, too. It's just that the other manifestations are so subtle or not immediately obvious that we don't recognize them. Through our work and that of our colleagues, we can begin to better define these conditions."

Bob Kuska | EurekAlert!
Further information:
http://www.nidcr.nih.gov
http://www.nih.gov

Further reports about: SUMO1 birth defect cleft cleft lip clefting individual newborn translocation

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>