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UCLA geneticists discover gene that controls cell growth

Robin Wulffson MD's picture
genetics research, tumr growth, IMAGe syndrome, Beckwith–Wiedemann syndrome

UCLA geneticists have discovered a gene involved in cell growth. The finding could lead to new ways to block the rapid cell division that allows tumor cells to have unrestrained growth. The findings were published in the May 27 edition of the journal Nature Medicine.

In addition to possible benefits for cancer treatment, the discovery could lead to the development of a method to diagnose children with IMAGe syndrome, which results in stunted growth. Interestingly, the mutation causing the syndrome occurs on the same gene that causes Beckwith–Wiedemann syndrome, which makes cells grow too fast, resulting in unusually large children.

Principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics, and urology at the David Geffen School of Medicine at UCLA, is particularly interested in the IMAGe syndrome. Almost 20 years ago, he was in residency training in his native France. At the time, he cared for two boys, ages three and six, who were unusually short for their ages. Although unrelated, the boys both had similar growth problems: minimal fetal development, stunted bone growth, sluggish adrenal glands, and undersized organs.

The children’s abnormalities made a lasting impression on Dr. Vilain. After joining the UCLA staff as a genetics fellow, his mentor at the time, Dr. Edward McCabe, mentioned a similar case from his previous position at Baylor College of Medicine. The geneticists were able to obtain blood samples from the three children and subjected them to DNA analysis for mutations; however, they were unsuccessful. Despite their unfruitful analysis, the two doctors published the first description of the condition, which they dubbed IMAGe syndrome in the Journal of Clinical Endocrinology and Metabolism and in 1999 published the first description of the syndrome, which they dubbed IMAGe, which was an acronym of sorts for the condition's symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies. Over the next decade, approximately 20 more IMAGe cases were reported from around the globe; however its cause was not determined.

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In 2011, a breakthrough occurred. Dr. Vilain received an email from Argentinian physician Dr. Ignacio Bergada, who had read the 1999 research paper. He described a large family he was treating in which eight members suffered the same symptoms described in the study. All of the family members agreed to send their DNA samples to UCLA for study. Prompted by this new information, Dr. Vilain assembled a team of UCLA researchers to partner with Dr. Bergada and London endocrinologist Dr. John Achermann. Dr. Vilain explained, At last, we had enough samples to help us zero in on the gene responsible for the syndrome. Sequencing technology had also advanced in sophistication over the past two decades, allowing us to quickly analyze the entire family's DNA samples.”

The researchers performed a linkage study, which identifies disease-related genetic markers passed down from one generation to another. The results steered them to a large segment of Chromosome 11. The UCLA Clinical Genomics Center performed next-generation sequencing, a powerful new technique that enabled the scientists to analyze the enormous amount of genetic material in just two weeks. They located a small area that contained the mutation. Furthermore, they located the same mutation in the original three cases described by Vilain and McCabe in 1999.

Dr. Vilain noted that the discovery of the gene responsible for IMAGe syndrome will allow the use of gene sequencing as a tool to screen for the disease and diagnose children early enough for them to benefit from medical intervention. Children born with Beckwith–Wiedemann syndrome grow very large, with big adrenal glands, elongated bones, and oversized internal organs. Because their cells grow so fast, one in five children with the disorder die of cancer at a young age. The disease appears in approximately one out of 15,000 births. Dr. Vilain noted that finding opposite functions in the same gene is a rare biological phenomenon.

IMAGe syndrome patients also tend to die young, due to poor adrenal activity, which physicians treat with hormone-replacement therapy. He noted that the IMAGe mutation's ability to miniaturize organisms and halt growth could offer intriguing clinical benefits. He explained that he and his team will now focus on manipulating the mutation's strong influence on growth to shrink tumors in the adrenal glands and other internal organs.

Reference: UCLA Health System