Todd P.
Dezen, (914) 997-4608, tdezen@marchofdimes.com Elizabeth Lynch, (914) 997-4286, elynch@marchofdimes.com
COLD SPRING HARBOR, NY, JUNE 13, 2013 – 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.
The
March of Dimes is the leading non-profit organization for pregnancy and baby
health. With chapters nationwide and its premiere event, March for Babies©, the March of Dimes works to improve the
health of babies by preventing birth defects, premature birth and infant
mortality. For the latest resources and information, visit marchofdimes.com or nacersano.org. Find us on Facebook and follow us on Twitter.
