NIH-funded study finds that gene appears to regulate protein signals inside the cell
Researchers working with mice have uncovered a potential clue to polydactyly a birth defect involving extra fingers on the hand or extra toes on the feet. The researchers have found that a mouse version of polydactyly results from a malfunction of the cellular machinery that processes one of the cell’s internal transportation vehicles. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health, provided funding for the study.
Polydactyly is estimated to occur in roughly 1 of every 500 to 1,000 births. The condition appears to result from a mutation in any of a number of genes. Polydactyly may involve only one extra finger or toe, or it may include multiple extra digits. The condition may also appear as part of a larger disorder having other organ abnormalities, some of which may be serious or life- threatening.
The study, published online in Cell Reports, was undertaken by Licia Selleri, M.D., Ph.D., Weill Cornell Medical College, New York City, and colleagues at Cornell and other institutions.
“Dr. Selleri and her colleagues have discovered that an unexpected cellular pathway is involved in the generation of extra digits,” said Lorette Javois, Ph.D., of the Developmental Biology and Structural Variation Branch at NICHD. “The findings expand what we know about genetic pathways involved in normal limb development and offer researchers a new direction in which to search for human mutations.”
Additional funding was provided by NIH’s National Institute of Dental and Craniofacial Research.
The researchers found that a mouse form of polydactyly appears to result from an error in a single gene out of a group containing the information needed to make a protein complex. The protein complex is called Endosomal Sorting Complex Required for Transport II — ESCRT-II, for short. Endosomes ferry molecules from the cell’s surface to the cell’s interior. When it functions normally, ESCRT-II processes endosomes for eventual disassembly within the cell. The mutation impairs the functioning of ESCRT-II, endosomes cannot be processed properly. As a result, an excess of a hormone known as fibroblast growth factor accumulates on the cell’s surface.
“Since this congenital defect appears both in isolation and in conjunction with other abnormalities, gaining fundamental knowledge of these genetic pathways is vital to developing effective genetic diagnostic screens and directed therapies,” Dr. Selleri said.