Specialty	Clinical Genetics - MD
Gender	Male
E-mail	robert.desnick@mssm.edu
Education and Training	MD, Univ of Minnesota-Med Sch. Minneapo
	Residency, Pediatrics, Univ of Minnesota-Med Sch. Minneapo
Awards	2009 Best Doctors New York Magazine

In the News

In this "Daily Check Up" feature from The Daily News, Dr. Desnick talks about treating genetic diseases.
View the PDF.

Education and Training	MD, Univ of Minnesota-Med Sch. Minneapo
	Residency, Pediatrics, Univ of Minnesota-Med Sch. Minneapo
Board Certification	Clinical Genetics - MD

Specialty	Clinical Genetics - MD
Board Certification	Clinical Genetics - MD

Gene Discovery
Using positional cloning and linkage analysis strategies, our previous efforts have resulted in the identification of several genes causing Mendelian disorders.  Current research is focused on several Mendelian disorders and complex traits including Crohn disease, a common inflammatory bowel disease. To identify the predisposing/susceptibility genes for complex traits, genome-wide association studies using 1 million SNP-DNA arrays and candidate gene approaches are being used. Studies of common complex traits will guide future predictive and preventive genetic strategies for improved, personalized health.

Molecular Genetics and Treatment of Lysosomal Storage Diseases
For the past two decades, studies of the lysosome and the pathogenesis and treatment of lysosomal storage diseases have been a major research theme of this laboratory. For example, in Fabry disease (galactosidase-Gal A] deficiency), our group isolated the human-Gal A gene, developed novel overexpression methods, and made knock-out mice with Fabry disease for preclinical studies of enzyme and gene therapy. These basic science studies provided the rationale for the clinical trials of enzyme therapy that proved effective in this disease. These studied culminated in approval of enzyme replacement for Fabry disease by the FDA in April 2003. Current studies are directed to: 1) identify and characterize the structure/function relationships of mutations in the Gal A gene which cause Fabry disease, 2) develop novel therapeutic strategies to treat Fabry disease and other disorders due to protein misfolding by rescuing/stabilizing the misfolded protein with small molecule pharmacologic chaperones, and 3) develop stem cell and gene replacement strategies for these diseases.

Pharmacogenomics
These studies involve the identification of variations in human genes responsible for the metabolism of drugs.  These variations cause the adverse drug responses that are common and often life-threatening.  Examples of the known genes with varying pharmacogenetic responses are the P450 genes.  By identifying the key genetic variations in an individual's genome that alter the activation, metabolism, transport, distribution and clearance of a given drug, a person's pharmacogenetic profile can be determined, permitting personalized drug selection and dosage.  Using single nucleotide polymorphisms (SNPs), candidate genes for a given drug are interrogated for informative haplotypes which are then tested in a given population of individuals experiencing adverse affects of the drug.  In addition, variations that alter drug metabolism can be tested in individuals taking the drug.

Molecular Genetics and Treatment of the Inherited Porphyrias
Heme biosynthesis requires eight enzymatic steps to convert succinyl-CoA and glycine to the final product, heme. All eight enzymes are encoded by nuclear genes, with the first and last three enzymes being located in the mitochondria while the second through fifth enzymes are in the cytosol. The inherited porphyrias are inborn errors of heme biosynthesis, each resulting from the deficient activity of a particular enzyme.  Previously, our laboratory: 1) developed assays, 2) purified these enzymes, 3) isolated and characterized the cDNAs and genomic sequences encoding several enzymes, and 4) identified molecular lesions causing the different porphyrias. Recently, we developed knock-in mouse models for an erythropoietic porphyria, congenital erythropoietic porphyria (CEP), and are currently developing knock-in mice to generate an improved mouse model for a hepatic porphyria, acute intermittent porphyria (AIP). These models will permit studies of the cutaneous and acute neurologic pathophysiologies of these porphyrias, and facilitate the development of novel therapies. Current therapeutic efforts in these models include hematopoietic stem cell therapy for CEP and AAV-8 mediated hepatic-targeted gene therapy for AIP.

Functional Genomics- Proteomics and Metabolomics
A major effort is underway to determine the functional genomics of the lysosome. Using high-resolution mass spectroscopy, the genes involved in human and/or murine lysosomal biogenesis and function are being identified. Novel methods have been developed to isolate lysosomes, perform 2-D gel electrophoresis to separate their membrane and soluble proteins, and then to identify each of the proteins using mass spectroscopy to sequence each of these proteins. In this way, novel proteins involved in lysosomal degradation and membrane biogenesis will be identified.

Gene Discovery, Functional Genomics, and Pharmacogenetics
Efforts are directed to exploit the Human Genome Project to: 1) identify genes underlying various Mendelian and complex (common) diseases, 2) identify candidate genes for complex (common) diseases by functional genomic, proteomic, and metabolomic strategies, and 3) identify pharmacogenomic variants in drug metabolism. 

Scott SA, Edelmann L, Kornreich R, Desnick RJ. Warfarin Pharmacogenetics: CYP2C9 and VKORC1 Genetypes Predict Different Sensitivity and Resistance Frequencies in the Ashkenazi and Sephardi Jewish Populations. Am. J. Hum. Genet 2008; 82: 495-500.

Cuhna L, Kuti M, Bishop DF, Mezei M, Zeng L, Zhou MM, Desnick RJ. Human uroporphyrinogen III synthase: NMR-based mapping of the active site. Proteins 2005; 71: 855-873.

Yasuda M, Domaradzki M, Bishop DF, Desnick RJ. Acute intermittent porphyria. Vector optimization for AAV-mediated gene therapy. J. Gene Med 2007; 9: 809-911.

Scott SA, Edelmann L, Kornreich R, Erazo M, Desnick RJ. CYP 2C9, 2C19, and 2D6 allele frequencies in the Ashkenazi Jewish population. Pharmacogenomics 2007; 8: 721-730.

Grace ME, Balwani M, Nazarenko I, Prakash-Cheng A, Desnick RJ. Type 1 Gaucher disease: Null and hypomorphic novel chitotriosidase mutations-implications for diagnosis and therapeutic monitoring. Hum. Mut 2007; 28: 866-873.

Germain DP, Waldek S, Banikazemi M, Bushinsky DA, Charrow J, Desnick RJ, Lee P, Loew T, Vedder AC, Abichandani R, Wilcox WR, Guffon N. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J. Am. Soc. Nephrol 2007; 18: 1547-1557.

Banikazemi M, Bultas J, Waldek S, Wilcox W, Whitley C, McDonald M, Finkel R, Packman S, Bichet D, Warnock D, Brenner BM, Desnick RJ. Algalsidase-beta therapy for advanced Fabry disease: A randomized trial. Ann. Intern. Med 2007; 146: 77-86.

Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ. High incidence of later-onset Fabry disease revealed by newborn screening. Am. J. Hum. Genet 2006; 79: 31-40.

Shabbeer J, Yasuda M, Benson SD, Desnick RJ. Fabry disease: Identification of 50 novel a-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum. Genomics 2006; 2: 297-309.

Bishop DF, Johansson A, Phelps R, Shady AA, Ramirez MM, Yasuda M, Caro A, Desnick RJ. Uroporphyrinogen III synthase knock-in mice have the human congenital erythropoietic porphyria phenotype including the characteristic light-induced cutaneous lesions. Am. J. Hum. Genet 2006; 78: 645-658.