Research

Division of Medical Genetics

The Division of Medical Genetics maintains an active basic science and clinical research program.

Inborn errors of metabolism are genetic disorders that affect the ability of the body to carry out vital biochemical reactions. These disorders affect two-to-three of every 1,000 people and their consequences range from neonatal death to chronic disease in adults. Discovering the underlying genetic cause of a group of these disorders involved in energy metabolism and amino acid catabolism is the focus of research being conducted by Gerard Vockley, MD, PhD, chief of the Division of Medical Genetics at Children’s Hospital of Pittsburgh. Dr. Vockley has identified numerous new disorders in the past decade and continues to focus on understanding structure and function of a family of enzymes known as the acyl-CoA dehydrogenases involved in fatty acid and amino acid metabolism. Novel therapeutic mechanisms are also under investigation. These and other fundamental questions are being investigated in Dr. Vockley’s laboratory through cellular and mouse models. Genomics, proteomics, and flux analysis techniques are providing new insight into a mechanism of disease that is likely to grow in importance as the understanding of gene interactions broadens. Three research faculty, Al-Walis Mohsen, PhD, Stephanie Mihalik, PhD, and Yudong Wang, PhD, bring additional expertise to this work.

Another Division of Medical Genetics faculty member David N. Finegold, MD leads a research team at the Graduate School of Public Health at the University of Pittsburgh that is investigating the genetic basis of lymphedema. Dr. Finegold’s work utilizes mapping and linkage techniques to identify loci containing genes that may be causal for the lymphedema phenotype. Once such genes are identified, mechanistic studies may then lead to an understanding of the effect of the protein product on lymphatic development and function. Such studies may also provide novel therapeutic strategies for treatment of lymphedema. He is also studying genes that contribute to complex phenotypes, such as the levels of thyroid hormones, as well as quantitative trait locus analysis of common traits such as height. In addition, Dr. Finegold participates in research in the Department of Chemistry aimed at developing novel biomolecular sensors. This work includes developing an ammonia sensor, which coupled with a phenylalanine sensor, will be helpful in the home management of patients with phenylketonuria.

Robert Nicholls, Phil. Doc. uses mouse models and human patients to study the phenomenon of genome imprinting and it’s derangement in human disease. Prader-Willi and Angelman syndromes are disorders caused by a complex defect of genomic imprinting on chromosome 15. The imprinted SNRPN locus is a complex transcriptional unit that encodes the SNURF and SmN polypeptides as well as multiple non-coding RNAs. SNRPN is located within the Prader-Willi (PWS) and Angelman syndrome region that contains multiple imprinted genes, which are coordinately regulated by a bipartite imprinting center (IC). The SNRPN 5' region co-localizes with the PWS-IC and contains two DNase I hypersensitive sites, DHS1 at the SNRPN promoter, and DHS2 within intron 1, exclusively on the paternally inherited chromosome. Dr. Nicholl’s has identified cis- and trans-acting regulatory elements within the endogenous SNRPN 5' region and allele-specific interactions with multiple regulatory proteins, including NRF-1, which regulates genes involved in mitochondrial and metabolic functions. Along with research faculty member Mihela Stephano, PhD, Dr. Nicholls is on the cutting edge of characterizing the complex mechanisms of disease related to these phenomena.