Dr. Van den Veyver's lab is focused on the following research:
Aicardi Syndrome was originally characterized by a triad of features, including agenesis of the corpus callosum (part of the brain is absent), chorioretinal lacunae (punched-out areas of the retina), and seizures, most commonly infantile spasms. Many affected children also have microcephaly (small head), axial hypotonia (decreased muscle tone), and appendicular hypertonia with spasticity on neurological examination. We see additional eye abnormalities in these children as well, including changes in the optic nerves, anophthalmia (missing eyes), and other changes in the retina. Other features include gastrointestinal difficulties, small hands, vascular malformations and pigmentary lesions of the skin, increased incidence of tumors, characteristic facial features, lower growth rate after ages seven to nine years, and precocious or delayed puberty.
Not every child with Aicardi Syndrome will have the exact same features. There is much variation in the physical effects of the condition and survival rates. The mean (average) age of survival is 8.3 years and the median age of survival is 18.5 years. In general, this syndrome affects only females, except in rare cases of boys with Klinefelter syndrome (47,XXY). For more information regarding why this disease is most commonly seen in girls, see Introduction to the Genetics of Aicardi Syndrome.
Research Update
We have been looking for genetic changes that may be the cause of Aicardi Syndrome using a new method, microarray-based comparative genomic hybridization (array-CGH). This technique involves a DNA chip, the size of a microscope slide, with hundreds of thousands of small pieces of DNA attached to it. A DNA sample from a girl with Aicardi Syndrome can be tested against the DNA on this chip. When a small piece of DNA in the tested sample is missing or has an extra copy, it will give a weaker or stronger signal on the DNA chip. By comparing the signals of DNA from many girls with Aicardi Syndrome to those who do not, we may be able to find the critical region in the DNA that contains the Aicardi Syndrome gene. Currently more than 20 DNA samples have been tested in our laboratory using this method and we are analyzing the results. We hope that this will point us to an area of DNA with a smaller number of genes that we then can study further to find the one that causes Aicardi Syndrome.
In another ongoing laboratory project, we are performing a large study of X-chromosome inactivation on DNA samples of Aicardi Syndrome girls to determine if there is skewed X-chromosome inactivation (XCI). Our current understanding of Aicardi Syndrome suggests that the genetic change in people with this syndrome is located on the X chromosome. Whether skewed XCI is present in Aicardi Syndrome has been a matter of some debate that we are trying to address with this larger study. Our results so far suggest that girls with Aicardi Syndrome may have more skewing of XCI. The initial results of this work were presented at the 2006 annual meeting of the American Society of Human Genetics.
Another aspect of our research involves selecting good candidate genes on the X chromosome that we then test in detail in the DNA samples of girls with Aicardi Syndrome. The decision to select a particular gene out of the ~1000 genes on the X chromosome is based on what we know about the function of the gene and how it compares to what we know about the medical problems in girls with this condition. Our ongoing work to analyze all the information of medical problems in Aicardi Syndrome is an important component of our research. Participation of families is extremely helpful to our progress. We continue to enroll new families in our study and appreciate the medical records and information provided by participants in our study.
As part of this work, Dr. Bobbi Hopkins, one of our research team members, has performed a study on the brain imaging findings (MRI, CT-scan) in Aicardi Syndrome that will be published soon. Tanya Eble and Dr. Richard Lewis are preparing a paper on the eye findings and Dr. V. Reid Sutton has published a paper on the facial and physical features of this syndrome. Drs. Sutton and Van den Veyver recently wrote a summary on Aicardi Syndrome for Genereviews.org, and hope that this will generate an increased awareness among health care professionals, which will lead to faster and more accurate diagnoses for families. We also assisted in the writing of Ande Glasmacher’s paper, which reviewed features and treatment of Aicardi Syndrome from collected family survey information. This paper is a great tribute to the initiative of the group and the efforts being made together to help families with Aicardi Syndrome by increasing awareness and providing health information about these children to further research.
In addition, Dr. Van den Veyver was successful in obtaining a research grant from the National Institutes of Health, specifically funded to study the genetic basis of Aicardi Syndrome. Overall, we are very encouraged by our progress and feel the outlook for our continued research is positive. Our current progress would not be possible without our enthusiastic study participants, and we thank all those who have joined our study on behalf of our entire research team.
A hydatidiform mole is an abnormal pregnancy, in which there is hyperplastic development of the placenta, which often develops into a mass of small vesicles or cysts. The name “hydatidiform” refers to its appearance as a “bunch of grapes”. In a complete hydatidiform mole, there typically is no embryo or fetus by the time it is clinically diagnosed, but in a partial hydatidiform mole there may be an embryo or fetus.
The most common form, complete hydatidiform moles (CHM) are usually sporadic. Interestingly, although these sporadic CHM have a normal number of chromosomes, the DNA that makes up the genetic information in the chromosomes of sporadic CHM is entirely paternally derived, without any maternally inherited DNA. Normally, we have 23 pairs or chromosomes or 46 chromosomes total, with one member of each pair of chromosomes inherited from the mother and one member of each pair inherited from the father.
However, in CHM there are also 46 or 23 pairs of chromosomes, but all are paternally inherited, resulting in their designation as “androgenetic” CHM. It is thought that in most CHM this occurs because the nucleus and the 23 chromosomes from the egg become inactive or disappear, while the 23 chromosomes coming from the fertilizing sperm duplicate to make 46 chromosomes.
Another possibility is that such an “empty” egg is fertilized by two sperm, each with 23 chromosomes. A partial hydatidiform mole (PHM) has 69 chromosomes, with three copies of each chromosome, wherein one copy is maternally inherited and two copies are paternally inherited. In these pregnancies there often is a fetus, but it usually has congenital malformations. This suggests that although identical in sequence, the maternally and paternally inherited member of each pair of chromosomes contribute differently to the developing fetus and placenta. It implies that the abnormal expression of imprinted genes, which are usually only expressed from either the maternally or paternally inherited chromosome is at the origin of the abnormalities seen in androgenetic CHM.
Research Update
Our laboratory is most interested in the study of a rare class of highly recurrent hydatidiform moles. These are usually CHM, although possibly sometimes PHM, that are indistinguishable from androgenetic sporadic CHM pathologically, but are quite different genetically: they have 23 chromosomes inherited from the father and 23 chromosomes inherited from the mother, just like a normally developing pregnancy, leading to the name “biparental” CHM. It was first found that these pregnancies have evidence of abnormal regulation and expression of imprinted genes.
Subsequently it was discovered that women who have these recurrent biparental CHMs have autosomal recessive mutations in a gene named NLRP7, located on chromosome 19 (refs are Murdoch et al, 2006 and Kou et al, 2008). It is believed that a general disruption in the regulation of genetic imprinting, either at the level of establishing imprinting marks in the egg or maintaining imprinting marks in the developing embryo and placenta is at the origin of the defects that lead to the biparental CHM. Our research is currently focused on understanding the mechanisms by which mutations in NLRP7 lead to the abnormalities that result in biparental CHM in women who have these mutations and how this may relate to mechanisms of reproductive loss in general. Another focus of our research on CHM focuses on the discovery of new imprinted genes by studying androgenetic CHM.
Goltz Syndrome, also known as Goltz-Gorlin Syndrome or Focal Dermal Hypoplasia, is characterized by patchy areas of dermal hypoplasia with deposition of subcutaneous fat into the dermis. Additional ectodermal features such as changes in the nail, skin, and hair are usually observed. Hair is often brittle and sparse. In addition, individuals with Goltz Syndrome may have skeletal and eye abnormalities. Typical ophthalmologic findings include colobomas, microophthalmia, and anophthalmia. Skeletal findings often include longitudinal grooving, ectrodactyly, syndactyly, brachydactyly, or oligodactyly. Mental retardation is present in approximately 15 percent of individuals. Some individuals may also have short stature, pointed chin, ear abnormalities, cleft lip and palate, hypodontia, diastasis pubis, kidney abnormalities, and midline abdominal wall defects. As it is an X-linked dominant disorder, approximately 90 percent of people with Goltz Syndrome are female.
Research Update
Goltz Syndrome is a condition caused by mutations in the PORCN gene at Xp11.23. This gene is part of the WNT pathway, as seen below. PORCN encodes the human homolog of the Drosophila melanogaster gene porcupine. Our investigation has revealed heterozygous and mosaic mutations in females and males, respectively (Wang, et al., 2007). Heterozygous changes were found in approximately 70 to 80 percent of females with confirmed or suspected Goltz Syndrome. Currently, sequence analysis is available for this condition on a clinical basis. Prenatal diagnosis is available when a familial mutation is known.
The Developmental Origins of Health and Disease hypothesis, also known as the Barker hypothesis, suggests that environmental factors at critical points in a person’s development can change their susceptibility to disease later in life. These epigenetic factors work not by changing the sequence of the DNA itself, but instead by altering the structure of the DNA strand or the methylation of particular genes, so that they are either “turned on” or silenced. The mechanisms by which this can occur are not yet completely understood, but much of the research being done shows a direct link between this developmental programming and maternal nutrition. Our lab focuses on maternal protein deprivation in mice during pregnancy and its effects on both the offspring’s phenotype and gene expression.
Research Update
In a recent study in our lab, we fed pregnant mice a low-protein diet and then measured the pups that were born for changes in body weight, organ weight, bone length, and gene expression. The most significant finding from this experiment was the overexpression of specific genes in the liver of adult offspring that are known to regulate transcription and organize the chromatin structure. These genes are part of the cohesin-mediator complex, a protein structure that helps bind promoters and enhancers on the DNA to form loops where activators can then transcribe the sequence. Nipbl, a gene encoding another protein that loads the loop-forming cohesins onto the chromosome, was also found to be highly expressed in the livers of these mice. These results point to new ways of thinking about maternal nutrition and how changes early on in life can cause genetic alterations as an adult.