The gene mutation that results in Goltz syndrome, also called Focal Dermal Hypoplasia – a developmental disorder affecting skin, bone, eyes and other body systems – occurs in a gene called PORCN, which is involved in the secretion of proteins necessary for proper signalling within the cell that leads to differentiation of tissues into organs and other body parts, said researchers at Baylor College of Medicine in Houston.
The finding, reported in the current issue of the journal Nature Genetics, is important both for the understanding of human development and for the patients who suffer from this rare disorder, said Dr. Ignatia B. Van den Veyver, associate professor of obstetrics and gynaecology and molecular and human genetics at BCM. It could lead to the discovery and better understanding of other disorders that may be associated with the same gene or with genes that have related functions.The research began when tests of two females who had the disorder identified an area of the X-chromosome that was deleted or missing. When the scientists determined the DNA sequences of genes in that area, they found mutations in PORCN in other girls with Goltz syndrome.The severity of problems resulting from the mutated gene, found on the X chromosome, vary, said Van den Veyver. There can be relatively minor to severe hand and foot abnormalities as well as those affecting the long bones of arm and legs. People with Goltz syndrome can suffer from skin defects on various body parts. In these cases, the skin does not develop normally, and fat, which usually stays under the skin, can come through, causing nodules. They can have eye abnormalities that may cause blindness in severe cases. Other organ systems are also affected.The variability occurs because the gene sits on the X chromosome. Each female has two X-chromosomes. Males have an X-chromosome and a Y-chromosome. There are many more genes on the X-chromosome than the Y. To insure that only one set of X-chromosome genes are activated to direct growth and development, the cells shut off or “inactivate” one of the X-chromosomes.In the case of the gene associated with Goltz syndrome, the severity of the developmental problem likely depends on the level to which the X-chromosome that has the abnormal PORCN gene is inactivated in girls.In most cases, Goltz syndrome is lethal in males. However, in some cases, males can have the problem because they actually have two populations of cells with a different genetic makeup, termed mosaicism. Most cases of mosaicism are believed to occur when there is an error in cell division early in foetal life.”The mosaic mutation had been hypothesised, but we were able to show it in this paper by testing DNA samples from four males with Goltz syndrome,” said Van den Veyver. “All had mosaic mutations.”PORCN provides the DNA blueprint for making a protein that in the fruit fly and mouse is called porcupine. This protein is critical to the secretion of Wnt proteins, which then contact the membranes of other cells, starting them on the pathway to differentiation into various organs, limbs and other structures in the body. At present, very little is known about the function of PORCN in humans or other animals and this discovery holds the opportunity to better understand this gene and its effect on the very important Wnt pathway.Understanding the protein and gene and confirming that it works the same way in humans that it does in animals is critical to further research, Van den Veyver said.”We would like to generate a mouse model of the syndrome to study the function of the protein in the mouse and investigate possible treatments,” said Van den Veyver.Others who took part in the research include Drs. Xiaoling Wang, V. Reid Sutton, Zhiyin Yu, Rebecca Rosetta, Ying-Chuck Kou, Tanya N. Eble, Ankita Patel, Christina Thaller and Ping Fang, all of BCM, and J. Omar Perza-Llanes of the Instituto Mexicano del Seguro Social in Merida, Yucatan, Mexico.Funding for this work came from the National Foundation for Ectodermal Dysplasias, the National Institutes of Health and the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center.(Source: Baylor College of Medicine : Nature Genetics : June 2007)