Our laboratory uses genetic approaches to try to understand the basis for selected single gene and more complex human developmental disorders. In 1999, we discovered that the X-linked, male lethal mouse mutants bare patches (Bpa) and tattered (Td) were associated with mutations in the genes Nsdhl and Ebp, encoding sequential enzymes in cholesterol biosynthesis. Subsequently, we and others identified mutations in the orthologous human genes in CHILD syndrome and X-linked dominant chondrodysplasia punctata, respectively. All of these disorders produce skeletal, skin, CNS, and eye abnormalities in surviving females and are among 6 known disorders of sterol biosynthesis. The most common of the human cholesterol biosynthesis disorders, Smith-Lemli-Opitz syndrome, causes hypotonia, failure to thrive, major malformations, mental retardation, and features of autism. Recently, several males with mental retardation and non-mosaic mutations in EBP or NSDHL have been identified, suggesting that the spectrum of phenotypes associated with defects in these genes is broader than originally thought, and that these enzymes play critical functions in the developing CNS.

Current projects in the laboratory are focused on understanding the mechanisms for the male lethality in Bpa mice, as well as the role of cholesterol deficiency on development of the brain and skeletal system. Our recent data demonstrate defective hedgehog signaling in placentas from affected embryos. In addition, we have demonstrated significant effects of the yolk sac and maternal environment on the embryonic phenotype using transgenic mice that overexpress a human NSDHL transgene. The transgenic allows us to compare embryos in which the affected X chromosome is transmitted by viable “rescued” males versus heterozygous dams. To examine the role of Nsdhl in the developing brain and skeleton, we have recently generated a conditional targeted allele in embryonic stem cells using Cre-lox technology. This conditional allele reproduces the null phenotype of the original Bpa mutation.

In a second project, we have initiated a large, collaborative project with Dr. Wolfgang Sadee at The Ohio State University and clinicians at Dayton Children’s Medical Center and Wright Patterson Air Force Base to develop a registry for families in central Ohio with children with autism spectrum disorders (ASDs), (CORA). Over 100 families have been enrolled with detailed demographic, genetic, and medical information on each. Through the registry and clinical genetics evaluations of children with autism, we have developed guidelines for genetic testing for newly diagnosed patients, including the sequencing of the PTEN tumor suppressor gene in patients with autism or developmental delay and macrocephaly. Finally, we are sequencing selected candidate genes for proteins involved in synapses in the brain in our autism registry families. Genes were chosen based on unique or rare genomic rearrangements detected on clinical microarrays.

Associate Professor, Department of Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio (joint appointment)