For an unknown number of parents each year, a mutation or "misprint" or a deletion in a gene called FOXF1 results in an infant born with a dangerous and uniformly fatal lung disease called alveolar capillary dysplasia with misaligned pulmonary veins (ACD/MPV).
An international group of researchers led by those at Baylor College of Medicine has analyzed the 42 mutations in FOXF1 in DNA from infants with the disorder and in a report that appears in the journal Human Mutation recommends that genetic testing be considered in infants with persistent pulmonary arterial hypertension with no known cause. This global collaboration involves samples from patients in 13 countries and 10 states. BCM is the prime institute involved in research related to this disorder and has the largest collection of DNA and tissue samples in the world.
"Most of the cases are spontaneous, meaning that they occur for the first time in the infant affected," said Dr. Partha Sen, an assistant professor of pediatrics - newborn at BCM and corresponding author of the report. However, reports on the rare cases in which the disease occurs in families can help understand the background of the disease, he said.
Many of the children with the disease can also have other anatomical problems involving organs of the gastrointestinal, cardiovascular and genitourinary systems.
In one family described by Sen and colleagues in a recent report in the European Journal of Human Genetics, five of six children died of the disorder soon after birth. Tests of DNA from three infants who died of the disorder showed that they had the same mutation in FOXF1 as did their mother. The healthy surviving sibling had a wild type gene (normal with no mutation) on chromosome 16. The mother had no evidence of the disease.
It appeared, said Sen, that the mutation was a new one (called de novo) that occurred on the chromosome the mother inherited from her father (the paternal chromosome). However, her affected children inherited the mutated chromosome from her - the maternal chromosome for them. The healthy child had the other chromosome 16 from his mother which she (mother) inherited from her mother (grandmother).
The affected children developed the disorder because of genomic imprinting of FOXF1 in human lung. In this case, the copy of the gene inherited from the father is silenced and the gene from the mother is the active copy - but it is a mutated copy.
In the exhaustive study of 42 new FOXF1 mutations in patients with this disorder, most were sporadic and not inherited from parents. However, among them were four familial cases and in three of those families, the infants inherited their mutated gene from the mother. Again, this buttresses the argument for genomic imprinting, said Sen.
BCM and the Texas Children’s Hospital are centers of study for the disease, an interest that began when Dr. Claire Langston, distinguished service professor emeritus of pathology at BCM, first became interested in the disease many years ago. In 2009, Sen, Langston, and Dr. Pawel Stankiewicz, associate professor of molecular and human genetics at BCM were co-authors on a paper that first identified that alveolar capillary dysplasia with misaligned pulmonary veins results because of alterations (mutations and deletions) in FOXF1, a transcription factor, a protein that binds to specific DNA sequences, controlling how DNA is transcribed into messenger RNA - the first step in translating the information in a gene into a protein, the workhorse of the cell. They now estimate that alterations in this gene account for approximately 80 percent of the cases of the disorder.
While the disorder is not common, Sen is not convinced that it is as rare as it was thought to be previously.
"I get two to three requests each month from around the world, asking to have the test run and the rise in the number of patients is the result of awareness that has been brought by the research at BCM," he said. Sen concentrates on mutations in the gene and Stankiewicz on deletions. He acknowledges that their work is indebted to the Alveolar Capillary Dysplasia Association (ACDA), a parent organization that has helped in bringing awareness to this deadly neonatal disorder. ACDA has also raised substantial amount of funds to support research.
Very few infants have received lung transplants because they are difficult to perform and obtaining an organ for an infant who is five to six weeks is challenging.
BCM researchers who took part in these studies include Sen; Yaping Yang; Colby Navarro; Przemyslaw Szafranski; Avinash V. Dharmadhikari; Debra Kearney; Binoy Sivanna; Michael L. Baker; Langston; Stephen Welty; John Belmont and Stankiewicz. All of the physicians in this study also practice at Texas Children¹s Hospital.
Funding for this work came from the National Organization for Rare Disorders, a Pilot Project Award from Texas Children’s Hospital to Sen, and the National Institutes of Health (NIH1R01HL101975-01) to Stankiewicz.