Owen M. Rennert, MD, Chief

The Laboratory of Clinical Genomics (LCG) focuses on the interface between biological and clinical research with respect to the process of development/differentiation. The LCG uses genomic approaches to understand the regulation of gene expression, cellular proliferation, and differentiation in mammalian development in health and disease.

In the past year, the Section on Developmental Genomics, led by Owen Rennert, established an expression database of mouse male germ cells and developing embryonic gonads through the use of Serial Analysis of Gene Expression (SAGE) and microarrays. The laboratory cloned several genes, among which the novel gene mArd2 demonstrated testis-specificity and elevated expression in pachytene spermatocytes. Subsequent studies showed that Ard2 has acetyltransferase activity and may be responsible for compensating for the loss of X-linked transacetylation activity during meiosis and post-meiotic differentiation in germ cells. Analysis of the germ cell database revealed the prominent presence of antisense transcripts. Of particular interest is the existence of antiparallel transcription unit pairs; such unit pairs may interact through hybridization between a transcript and the pair's antisense transcript, the latter being derived from the pseudogene embedded in the intron of the former. Mapping the transcriptome of murine male embryonic gonads has allowed the creation of a chromosome heatmap of gonad development that permits researchers to highlight chromosomal "hotspots" with significant gene activities at any time of development. The chromosome heatmap will be useful for identifying the importance of different regions at specific time points during the development process as well as for determining the potential consequences of chromosome duplication or deletion. Related to these studies of mouse development is a study of the role of luteinizing hormone/choriogonadotropin receptor (hLHR) in human development and diseases. Studies in cell models uncovered a novel role of hCG in neuronal development. Expression profiling revealed distinct genes and, hence, physiological changes triggered by two different mutations of the same amino acid in hLHR. Members of the Section also applied genomic approaches to the study of human diseases, designing two hybridization-based high-throughput methods for screening susceptible risk factors for thrombophilia and age-related macular degeneration. The devices based on this approach will provide a more accurate tool for risk calculation and disease prediction for these two complex disorders.

During the past year, the Unit on Pediatric Genetics, led by Stephen Kaler, investigated two groups of disorders: the X-linked recessive disorder called Menkes Kinky Hair disease and the platelet abnormality known as Bernard-Soulier syndrome. In the case of Menkes Kinky Hair disease, the Unit investigated gene-expression consequences of a defect in the copper-ATP7A transport system in clinical autopsy material and used a yeast complementation assay to assess residual copper transport capacity by specific Menkes disease (ATP7A) mutant alleles. The investigators studied a child who had the velo-cardio-facial syndrome with thrombocytopenia due to haploinsufficiency of chromosome 22q11. The research led to the further delineation of the GPIb alpha-GPIb beta-GPIX platelet glycoprotein complex.