Biochemistry & Molecular Biology
Keck School of Medicine
Institute for Genetic Medicine
School of Dentistry
- Small molecule/drug screen
- Neurological disease
- Human/Mammalian Genetics
- Molecular Epidemiology
Research OverviewThe central theme in my laboratory has been to dissect the genetic basis of inherited diseases particularly those involving the nervous system. Given a particular disease phenotype, we have sought answers to one or more of the following questions:
1) What is the underlying gene(s) and the associated defect?
2) How is the gene regulated in the normal and the diseased state?
3) What are the diagnostic options?
4) How can the discoveries be used for developing therapies?
Focusing on these questions, my lab has identified novel mutational mechanisms that underlie several inherited disorders that affect the nervous system, dentition or hair growth. This has allowed the development of DNA-based tests that have been very helpful to patients and clinicians world-wide. Other disorders for which genes are being sought include familial myasthenia gravis, frontotemporal dementia and several craniofacial disorders. Our current efforts are focused on:
Therapeutic strategies for Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy that affects about 1 in 2500 people. The disorder affects both motor and sensory nerves that carry signals to and from muscles and sensory organs, respectively, in the limbs. Symptoms include progressive weakness of the foot and lower leg muscles which cause gait imbalance and muscle atrophy in the hands which affects fine motor skills. Pain and numbness can range in severity. Other than corrective surgery and braces, there are no other treatments for CMT.
Mutations in over 45 genes have been associated with CMT. The first of these genes was identified after we discovered a DNA duplication of 1.5 million bp on chromosome 17 in patients with CMT1A, a subtype of CMT that affects > 50% of all CMT patients. This unprecedented mutational mechanism we discovered leads to the over-expression of the gene for the peripheral myelin protein, PMP22. We also discovered that in a minority of CMT1 patients, the disorder is caused by a point mutation in PMP22. Following up on our discoveries from the '90s and with the availability of new screening technologies, we have recently developed an assay that has been used to screen small molecule libraries towards identifying lead compounds that could be used to treat CMT1A. The top “hits” from the screen have been used in medicinal chemistry studies to develop analogs in order to identify the best “lead compounds” for further investigation. Current studies are focused on (1) determining the mechanism of action of these molecules using biochemical and cell biological approaches (2) developing assays for in vivo analysis to assess the small molecules (3) examining the intra-cellular interactions of normal and mutant PMP22 proteins and the effect of these candidate small molecules on these interactions.
Genetic structure of Asian Indian populations: Relevance to dissection of complex diseases
Although the prevalence of complex genetic diseases in Asian Indians such as coronary artery disease(CAD) is very high, these populations had not been incorporated in any large-scale genomic surveys. The questions we asked were: (1) how does the genetic structure of Asian Indians vary among individuals speaking 15 different languages (2) how does it compare with other world populations (3) are the restricted marriage practices (“exogamic endogamy”) among certain Indian populations reflected in their genetic structure and can this be utilized for the study of complex diseases such as heart disease? We found that populations from India, and those from South Asia more generally, constitute one of the major human ancestry subgroups. Studies on one population practicing endogamy have revealed the fine-scale genetic structure and further validated the utility of such populations for dissection of complex diseases such as CAD. Ongoing whole genome sequencing of this population will allow us to address specific questions such as prevalence of drug sensitivities and dissection of genes that predispose them to common diseases such as CAD or type 2 diabetes.