In rare instances, a woman will have all the signs and symptoms of pregnancy, but the pregnancy does not develop normally. Instead, she has a hydatidiform mole, a mass that results from overproduction of tissue that is supposed to become the placenta, and an embryo that fails to develop normally. Such moles have to be removed surgically because they can cause serious health complications.
In a report in the journal Human Molecular Genetics, Dr. Ignatia B. Van den Veyver, vice chair of research in the Department of Obstetrics and Gynecology at Baylor College of Medicine and the Texas Children’s Pavilion for Women, and her colleagues unraveled the first clues as to how loss or mutation of a gene called NLRP7 in women can cause their pregnancies to develop as hydatidiform moles.
The genomes of hydatidiform moles have abnormal imprinting and this is thought to ultimately cause the pregnancies to develop abnormally, but how exactly this happens and what this means to future fertility has long puzzled scientists and physicians.
Most people inherit two copies of a gene – one copy from the mother and the other from the father. In most genes, both copies work. However, some genes are imprinted, which means that either the mother’s copy or the father’s copy is turned off, often through a molecular activity called methylation. In most cases, imprinting is abnormal in hydatidiform molar pregnancies because they only contain DNA inherited from the father, and none from the mother.
However, Van den Veyver and her team study a rarer form called biparental hydatidiform moles in which the DNA is inherited from both parents, but the imprinted genes still behave abnormally. In previous published work, it had been shown that in many cases, these rare biparental hydatidiform moles happen when women have mutations in the gene called NLRP7. How loss of NLRP7 function causes these abnormal pregnancies with imprinting abnormalities was still not known.
Studying this was difficult. Mice lack the gene and could not be used as laboratory model. However, in studies in federally approved embryonic stem cells lines, they found that lowering the levels of the protein made by the NLRP7 gene accelerated the differentiation into trophoblast cells (the outermost layer of cells of the blastocyst that attaches the fertilized ovum to the uterine wall) and serves as a nutritive pathway for the embryo, and also altered DNA methylation.
Sangeetha Mahadevan, a graduate student in the Translational Biology and Molecular Medicine Program at BCM and co-first author of the report, said it’s interesting to think of a gene like NLRP7, which belongs to a gene family involved in innate immunity, as having this kind of effect.
A normal pregnancy is almost impossible for women with this problem, she said. The women who have two faulty copies of the NLRP7 gene may never know that is so until they try to have children. She and Van den Veyver think that something in the development of the egg itself that affects imprinting is preventing normal pregnancy.
“We have some interesting data now that supports that this protein that really was not previously thought to directly affect the imprinting mechanism is actually capable of changing DNA methylation,” said Van den Veyver. “We still need to do a lot of work to get to the bottom of the story, and how this relates to how imprinting is regulated in germ cells.”
The story itself may have more implications.
“While this is a rare disease, by understanding what this and similar proteins do, we can unravel how imprinted genes are recognized in the germ line (eggs and sperm) as being imprinted and how sequences are recognized that need to change methylation when they are passed on to the next generation,” she said.
Others who took part in this work include: Shu Wen,Hsiu-Huei Peng, Subhendu Otta and Zhandong Liu, all of BCM; Ying-Wooi Wan and Bekim Sadikovic of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and BCM; Michelina Iacovino, Elisabeth M. Mahen and Michael Kyba, all of Lillehei Heart Institute and Department of Pediatrics at the University of Minnesota in Minneapolis.
Peng is now with Chang Gung University in Tao-Yuan, Taiwan; Otta with Central Institute of Brackishwater Aquaculture in Puram, Chennai, India; Iacovino is now with Harbor-UCLA Medical Center in Torrance, Calif., and Sadikovic is with McMaster University in Hamilton, Ontario, Canada.
Funding for this work came from the National Institutes of Health (Grants R21HD058081;R01HD045970 and NIH 5P01GM081627); the U.S. Food and Drug Administration Agricultural Research Service (Grant 6250-51000-055); the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (BCM IDDRC Grant Number 5P30HD024064) and the National Center for Research Resources (Grant Number C06RR029965).