Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

First gene for clubfoot identified

27.10.2008
Clubfoot, one of the most common birth defects, has long been thought to have a genetic component. Now, researchers at Washington University School of Medicine in St. Louis report they have found the first gene linked to clubfoot in humans.

Their research will be published in the Nov. 7 issue of the American Journal of Human Genetics.

By studying a multi-generation family with clubfoot, the scientists traced the condition to a mutation in a gene critical for early development of lower limbs called PITX1. While other genes are also likely to be linked to clubfoot, the new finding is a first step toward improved genetic counseling and the development of novel therapies.

"To our knowledge this report is the first evidence for PITX1 mutation in human disease," said Christina Gurnett, M.D., Ph.D., assistant professor of neurology, of pediatrics and of orthopedic surgery at the School of Medicine. "Once we identified the mutation, we proved that all of the individuals in this family with lower extremity malformations also have the mutation. Having large families to work with is very helpful in genetic research."

Gurnett and her colleagues analyzed the DNA of 35 extended family members of an infant male patient of Matthew Dobbs, M.D., associate professor of orthopedic surgery at the School of Medicine and a clubfoot specialist at St. Louis Children's Hospital and St. Louis Shriners Hospital. The patient, the most severely affected in the family, had clubfoot in both feet, duplicated first toes and was missing the tibia in the right leg.

Gurnett and Dobbs visited the family members in their community to examine their lower limbs and to take DNA samples. They found that 13 family members were affected: Five additional family members had clubfoot, which was more severe in the right foot in three of them. Five others had lower limb abnormalities including flatfoot, an underdeveloped patella and hip dysplasia.

Through the genome-wide study, Gurnett and her colleagues found a region on chromosome 5 that was common to all family members affected. From there, they identified a mutation in a gene critical for early development of lower limbs called PITX1. The PITX1 mutation was found in all affected family members and in three carriers who showed no clinical symptoms.

Dobbs, senior author of the study, said the finding is an exciting step in developing a better understanding of the genetic basis of clubfoot, which affects about 1 in 1,000 new births.

"Clubfoot is a complex disorder meaning that more than one gene as well as environmental factors will be discovered to play a role in its etiology," Dobbs said. "Identifying the genes for clubfoot will allow for improved genetic counseling and may potentially lead to new and improved treatment and preventive strategies for this disorder."

Dobbs treats children with clubfoot and other orthopedic abnormalities using the Ponseti method, a treatment that involves weekly casting and the manipulation of clubfoot soon after birth. In 2007, Dobbs developed a new dynamic brace called the Dobbs brace for clubfoot that allows active movement, preservation of muscle strength in the foot and ankle and fewer restrictions on the child than the traditional brace.

About 80 percent of clubfoot cases are idiopathic, meaning the cause is unknown and the patient has no other birth defects. A familial link plays a role in about 25 percent of cases. The condition occurs in males twice as often as in females and occurs more often in the right foot. About half of the cases affect both feet, including the bones, muscles, tendons and blood vessels. If untreated, those affected walk on the outside of their feet, which can lead to long-term pain and disability.

Gurnett said some clinical characteristics of the family members with the PITX1 mutation suggest that the genetic defect may be linked to idiopathic clubfoot. First, the majority of the affected family members had clubfoot, but no other abnormalities. Second, there were five females who carried the gene but did not have clubfoot, which supports the lower incidence of clubfoot in females. Third, clubfoot affects the right foot more frequently, a hallmark of mutations in PITX1.

Previous studies had shown a relation between PITX1 and the development of hindlimbs in other vertebrates. In mice, a loss of PITX1 leads to shorter femur length and fewer digits on the right foot than on the left. An alteration of the gene in a developing chick wing changes it so that it looks more like a leg. In vertebrates such as the manatee and stickleback fish, an alteration has resulted in evolutionary changes in the development of the pelvis.

"It's our job to prove that this is going to be important for many kids with clubfoot," Gurnett said. "Until now, we didn't know whether clubfoot was a muscle, nerve, spinal cord or brain problem. Now, we have an idea that clubfoot may result from mutations of genes that are involved in early limb development."

Gurnett said she and her colleagues will take the finding back to the lab to look for other factors involved in the pathway or how environmental effects may influence the gene. She and Dobbs, who have been studying the genetics of clubfoot for a decade, plan to investigate the frequency of PITX1 gene mutations in other families with clubfoot.

Gurnett C, Alaee F, Kruse L, Desruisseau D, Hecht J, Wise C, Bowcock A, Dobbs M. Asymmetric Lower-Limb Malformations in Individuals with Homeobox PITX1 Gene Mutation. American Journal of Human Genetics, 7 Nov. 2008.

Funding from the National Institutes of Health, The Children's Discovery Institute, the March of Dimes Basil O'Connor Starter Scholar Research Award, St. Louis Children's Hospital Foundation, Pediatric Orthopaedic Society of North America and Shriner's Hospital supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Beth Miller | EurekAlert!
Further information:
http://www.wustl.edu

More articles from Life Sciences:

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

nachricht When fish swim in the holodeck
22.08.2017 | University of Vienna

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Molecular volume control

22.08.2017 | Life Sciences

When fish swim in the holodeck

22.08.2017 | Life Sciences

Biochemical 'fingerprints' reveal diabetes progression

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>