Scientists discover the gene that causes a rare growth-inhibition syndrome

A study conducted by an international group of scientists, including Brazilian researchers, has identified the gene that causes IMAGe syndrome, an acronym for intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. The study was published in the journal Nature Genetics.

By Fábio de Castro

Agência FAPESP – A study conducted by an international group of scientists, including Brazilian researchers, has identified the gene that causes IMAGe syndrome, an acronym for intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. The study was published in the journal Nature Genetics.

Patients with IMAGe, which until now had an unknown etiology, have a low body weight at birth, adrenal insufficiency, and skeletal and genital alterations.

According to the authors, the study revealed a previously unknown molecular mechanism. Although IMAGe is an extremely rare genetic syndrome, the discovery could be useful for understanding more prevalent diseases.

According to one of the authors, Bruno Ferraz-de-Souza, a researcher at the Universidade de São Paulo (USP) Medical School, mutations of the CDKN1C gene had already been described as the cause of a more common syndrome characterized by excess growth. In the new study, scientists discovered that the gene is also responsible for IMAGe syndrome, which involves growth restriction.

“We have been looking for the cause of IMAGe syndrome for many years. In this study, utilizing parallel sequencing (analyzing DNA samples from an Argentinean family with many affected members and samples collected from other patients over the past 20 years) we discovered that the syndrome is caused by a specific mutation of the CDKN1C gene, in chromosome 11,” commented Ferraz-de-Souza in an interview with Agência FAPESP.

Scientists participating in the study included researchers at the University of California at Los Angeles,  University College London and Hospital de Niños Ricardo Gutierrez in Argentina.

According to Ferraz-de-Souza, CDKN1C was already known to play an important role in the regulation of cellular growth. Mutations of CDKN1C had already been associated with Beckwith-Wiedemann syndrome, which causes abnormal growth of certain regions of the body and of organs, exacerbating the risk of tumor development.

“Now we know that the same gene that causes the hyper-growth syndrome is also responsible for this rarer syndrome of reduced growth,” he says.

The alterations that were discovered in Beckwith-Wiedemann syndrome are spread throughout every region of this gene. The mutations that cause IMAGe syndrome, however, occur only in a very limited region, of six amino acids. “A simple change in the position of this region determines completely different phenotypes,” says Ferraz-de-Souza.

A genetic factor made the discovery more complex: expression of the CDKN1C gene is controlled by imprinting, which means that the disease manifests only when inherited from the mother. A person who inherits the mutation from his or her father will not develop the disease but can pass the mutation to his or her children.

“The mechanism by which this mutation occurs in the six disease-causing amino acids remains unknown. But it is possible that the mechanism is  relevant to the study of, for example, tumorigenesis and other genetic alterations that cause cancer. The discovery of rare disease mechanisms can be relevant when applied to more prevalent diseases,” says Ferraz-de-Souza.

The first part of the study was conducted based on a DNA analysis of an Argentinean family with at least four generations of individuals who were either affected or unaffected by the syndrome. Based on samples from this family, the scientists in the U.S. team conducted SNP arrays to delimit the chromosome region in which the promoter of the disease-driving gene was likely to be located, and they began to apply parallel sequencing techniques.

“After studying the Argentine family, we suspected that the cause was mutations of the CDKN1C gene. In these cases, it is standard practice to look for other individuals with the same phenotype as a means of confirming that the right gene has been identified,” says Ferraz-de-Souza.

At the time of the study, Ferraz-de-Souza, who was pursuing his doctorate at University College London, was attempting to identify genes that caused a rare adrenal disease.

“In England, we had DNA samples from patients with the phenotype that the North American group was seeking. They contacted us and confirmed that the mutation always occurred in the same six amino acids,” he explains.

“As abortion is legal in the United Kingdom, the British team had access to fetal material. With this, it was possible to show through histochemistry and quantitative PCR that the gene was in fact expressed in a normal adrenal gland during development. It is possible that the CDKN1C gene is very important for normal adrenal growth,” Ferraz-de-Souza  says. 

Other diseases

In the final part of the study, the scientists conducted functional studies to show that changes to the gene cause changes to the phenotype.

“We conducted experiments with Drosophila flies. The introduction of mutations in this gene [CDKN1C] resulted in flies with a drastic reduction in the size of the eyes and wings. This confirmed that alterations in that exact position of the gene caused growth deficiencies,” says Ferraz-de-Souza.

Ferraz-de-Souza, wanted to understand why alterations in such a small portion of the DNA caused such severe mutations. “This is a very interesting research field and could lead to understanding similar mechanisms that might be involved in other hyper-growth diseases,” he says.

Back in Brazil, Ferraz-de-Souza is conducting studies on defects in the vitamin D receptor and skeletal diseases, with FAPESP’s support through Young Investigators in Emerging Centers.

“Although this is a different line of research, it is possible to continue to collaborate on research on the IMAGe syndrome since skeletal alterations are one of the syndrome’s manifestations,” he said.

The article Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome (doi:10.1038/ng.2275) by Eric Villain et al can be read by subscribers to Nature Genetics at www.nature.com/ng/journal/vaop/ncurrent/full/ng.2275.html.