Musculoskeletal Inherited Disease

Vicky L. Funanage, Ph.D. Laboratory Head

Major Research Interests

The laboratory focuses primarily on the molecular genetic analyses of pediatric neuromuscular diseases and the development of novel therapies for these disorders. One project involves the use of the compound hemin as a possible treatment for muscular dystrophy. Past research has shown that hemin increases the expression of muscle-specific genes and decreases the fibrosis associated with muscular dystrophy (U.S. Patent 5,604,199). In work conducted in the dystrophic dog model, intravenous administration of hemin showed positive trends in improving muscle strength; however, further work showed that very little of the administered hemin was reaching skeletal muscle. Together with Dr. Tatiana Samoylova of Auburn University, the MID laboratory is working on a novel method that is expected to increase the delivery of hemin to muscle tissue.

The second area of interest involves spinal muscular atrophy, the second most common genetic cause of muscle weakness and wasting in children. This research, done in collaboration with the MID Laboratory has also provided important contributions toward understanding the genetic and biochemical basis of myotonic dystrophy (DM), an autosomal dominant disease characterized by progressive muscle weakness and atrophy, myotonia, cataracts, mental retardation, and cardiomyopathy. The genetic basis for DM is due to an increased number of CTG repeats in the 3 untranslated region of the DM protein kinase (DMPK) gene. The laboratory has shown that the CTG repeat expansion leads to a decrease in DMPK mRNA levels by affecting the regulation of splicing at the 3 end of the DMPK pre-mRNA transcript. Furthermore, the repeat expansion has a trans-negative effect on the expression and splicing of other mRNAs in terminally differentiated tissue, like skeletal muscle, heart, and brain.

The MID Laboratory is also studying leptin, an important hormone that regulates energy metabolism and utilization.

Additionally, the MID Laboratory is home of the Molecular Diagnostic Laboratory, which has entered its 12th successive year of Clinical Laboratory Improvement Act (CLIA) certification. In addition to DNA diagnostics tests for Duchenne/Becker muscular dystrophy (Dystrophin), Myotonic dystrophy , Spinal muscular atrophy (U.S. Patent 5,882,868), Barth syndrome (TAZ gene), and Pelizaeus-Merzbacher disease (PLP gene), the laboratory now offers testing for congenital deafness (CX26 and CX30),Rett syndrome (MECP2), Emery-Dreifuss muscular dystrophy(Emerin), Benign Hereditary Chorea (NKX2.1), Costello syndrome (HRAS), and CFC Syndrome (BRAF, MEK1 and 2).

Dr. Mena Scavina, Division of Neurology at Alfred I. duPont Hospital, has revealed increased expression of a protein called RAD (for ras associated with diabetes) in cells of spinal muscular atrophy patients. Overexpression of RAD has been shown to inhibit glucose uptake into tissues, providing a possible explanation for the muscle wasting and weakness seen in this disease. More recently, Dr. Wenlan Wang, Assistant Research Scientist, has demonstrated that fibroblast cells from SMA patients are more sensitive to the apoptosis inducing agent, camptothecin, which involves the caspase 3 pathway. Therapeutics for spinal muscular atrophy are, thus, focusing on ways to decrease expression of RAD and caspase 3, particularly in motor neurons and skeletal muscle. Sandra Hassink, M.D., Director of the Weight Management Program at Nemours Childrens Clinic-Wilmington, has shown that leptin is produced by both the placenta and mammary gland, indicating the importance of leptin in fetal and neonatal growth. In addition, results indicate that leptin augments surfactant production in fetal lung, and a patent application has been filed for the use of leptin in treatment of respiratory distress syndrome in infants, children, and adults. A relatively new collaboration has begun with Thomas Shaffer, Ph.D., Director of the Nemours Research Lung Center whereby the upregulation of surfactant proteins by various agents in the fetal lamb is being investigated as an alternative treatment in premature infant respiratory distress syndrome. A Nemours patent (U.S. Patent No. 6,475,984) was awarded last year for the administration of leptin, and another patent is pending regarding the use of leptin as a method for treatment of respiratory distress syndrome. Nemours Cardiac Center. We are exploring the genetic and biochemical basis for development of hypoplastic left heart syndrome in collaboration with Dr. Robert Akins of the TERM Laboratory and Dr.Christian Pizarro of the Nemours Cardiac Center.

Current Projects

• A Study of TAZ mRNAs In Barth Syndrome Individuals
• Expression of a Diabetes-Related Gene (RAD) in Spinal Muscular Atrophy
• Leptin Regulation of Lung Surfactant Production
• Spinal Muscular Atrophy with Respiratory Distress (SMARD1): Mutational Analysis
• Transcription Factors and Human Cardiac Malformations

Current Research Group

• Angelique P. Davis-Williams, MS - Angelique Davis-Williams primary focus is DNA diagnostics of Pelizaeus-Merzbacher Disease (PMD). Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder affecting myelin formation in the central nervous system. Our Molecular Diagnostics Laboratory offers clinical molecular diagnostics for both duplication and mutation of the PLP gene. An estimated 5% to 20% of patients with clinical findings consistent with PMD do not have a duplication or a mutation in an exon or intron-exon junction of the PLP gene.
• Iris L. Gonzalez, PhD - Iris L. Gonzalez, Ph.D., is a molecular geneticist who has been involved in teaching, research, and molecular diagnostics. Past research concentrated on ribosomal RNA genes and their evolution. Current research includes 2 projects: [1] identifying all the products of the G4.5/TAZ gene responsible for Barth syndrome, [2] identifying mutations in the IGHMBP2 gene responsible for Spinal Muscular Atrophy with Respiratory Distress. Molecular Diagnostics are a big part of her interests and, especially in the diagnostics for Barth syndrome, also lead to additional understanding of the disease.
• Sandra Hassink, MD
• Susan M. Kirwin, BS - Susan Kirwin is currently the Assistant Director for the Molecular Diagnostics laboratory. She continues studying transcription factors in hypoplastic left heart syndrome; the biochemical basis for development of cyanosis in patients with congenital heart malformations; effects of leptin and cc10 on fetal lung development; and muscle specific peptides and targeted delivery of hemin to skeletal and cardiac malformations.
• Priscilla A. Moses, MS, BS - Ms. Moses conducts DNA diagnostics for the Molecular Diagnostics Laboratory. These include Duchenne and Becker muscular dystrophy; Spinal Muscular Atrophy (SMA) and Myotonic Dystrophy. She is also involved in the culture of skin fibroblasts, which are utilized in the determination of several metabolic disorders.
• Darlise M. O'Connor- As a Research Associate, Ms. O'Connor is a member of the Spinal Muscular Atrophy team investigating the role that SMN plays in cell death of the motor neuron. The long-term goal is to understand the mechanisms by which the SMN protein protects motor neurons from apoptosis. In addition to research responsibilities, she participates in two departmental committees. She serves as coordinator for safety training and departmental inspections on the Research Safety Committee. Ms. O'Connor is also a member of the Research Radiation Advisory Committee.
• Wenlan Wang, MD, PhD

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