With support from a March of Dimes Foundation grant, scientists at Cold Spring Harbor Laboratory (CSHL) have solved the mystery of why some infants are born with a severe form of a rare birth defect involving cleft palate and major deformities of the skin and limbs, while other babies with the same genetic disorder have little or no sign of the condition.
Ectodactyly, ectodermal dysplasia, clefting syndrome (EEC) has a known genetic culprit, a single altered “letter” in the DNA comprising a gene called p63. The gene provides cells with instructions on making a protein, also called p63, that has several essential functions, including during early development. When the gene is mutated, so is the protein it encodes, leading to the birth defects seen in EEC.
EEC is autosomal dominant, meaning that only one parent needs to contribute the mutated copy of the gene for a child to develop the disorder. Each child of an affected parent has a 50 percent chance of having EEC.
“But the big question is why some children with the mutation have severe birth defects, while others—in some cases, siblings of those affected—who bear the same p63 mutation, are mostly or entirely symptom-free,” says Professor Alea Mills, PhD, the CSHL geneticist who led the team that has just solved this mystery.
A complex series of genetic experiments directed by Prof. Mills now reveals that the presence or absence of one variant type of the p63 protein, called TAp63, acts as a modifier to determine whether or not a child with the p63 mutation will in fact develop EEC symptoms.
TAp63 normally protects from the birth defects, and if it is not present, pathology is certain to occur, the team’s experiments showed. “The only way you can have the EEC mutation and be healthy, or have slight symptoms of the illness such as a bit of webbing between two toes, is to have robust amounts of TAp63 protein in cells when and where it is needed, during development,” says Prof. Mills.
She hopes that her team’s discovery that TAp63 affects the presence of birth defects will encourage doctors treating children with EEC to compare those only mildly affected with siblings or other children who have a severe form of the disease.
“It will be important to sequence DNA from these children and compare the results. What’s different? If we find differences, we have nailed it. If we find that ¬¬¬the sequences are exactly the same, then we might look at several factors regulating gene expression for evidence of how TAp63 is expressed differently in each group.”
“An Allelic Series of Trp63 Mutations Defines TAp63 as a Modifier of EEC Syndrome” appears June 14, 2013 in the American Journal of Medical Genetics. The authors are Emma Vernersson Lindahl, Elvin L. Garcia, and Alea A. Mills. The paper can obtained using the DOI 10.1002/ajmg.a.36074.
The research was made possible by grants from the March of Dimes Foundation; the American Cancer Society; the Swedish Research Council; and the Lauri Strauss Leukemia Foundation.