Pragna I. Patel Professor Biochemistry & Molecular Biology Keck School of Medicine Institute for Genetic Medicine School of Dentistry

Education:
BSc 1976 Chemistry, Botany, Zoology - Bangalore University, India
PhD 1982 Biochemistry - West Virginia University

Postdoctoral Research Fellowship:
Baylor College of Medicine
Howard Hughes Medical Institute

Started at USC: 2004

Research Topics: Human/Mammalian Genetics, Cardiovascular & Skeletal Muscle Diseases, Molecular Epidemiology, Neurogenetics

Research Description

The central theme in my laboratory is understanding the genetic basis of inherited diseases particularly those involving the nervous system. Given a particular disease phenotype, we seek answers to 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) What are suitable DNA-based therapeutic options?

Genetics of Neurological Disorders:
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. The subtype CMT1A is associated with a novel mutation consisting of a DNA duplication of 1.5 million bp on chromosome 17. Overexpression of the gene for the peripheral myelin protein PMP22 appears to underlie the demyelinating neuropathy in most CMT1A patients. Towards developing therapeutic strategies for correction of the CMT1A phenotype based on adjustment of gene dosage levels, we are studying the regulation of the PMP22 gene and defining the critical elements required for expression in Schwann cells versus other cell types.

Acquired autoimmune generalized myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, characterized by a post-synaptic blockade of the nervous transmission that manifests as weakness and fatigability of striated muscles. It can be life-threatening when bulbar or respiratory muscles are involved. Its main biological feature is the production of autoantibodies against the muscular acetylcholine receptor (AChR) in the majority of the patients. These autoantibodies are highly specific, their presence in the serum of a patient is a crucial diagnostic element and most importantly, they underlie the pathogenicity via the blockade of the neuromuscular transmission. The majority of MG cases are sporadic while approximately 1-4 % of cases are familial without a simple Mendelian pattern. The majority of familial cases are likely to be caused by congenital myasthenic syndromes, in which mutations directly affect proteins involved in neuromuscular transmission. However, autoimmune myasthenia gravis (AMG) may be very rarely inherited within a family. No gene underlying AMG has been identified. We are studying a very rare family segregating autoimmune familial myasthenia gravis. Elucidation of the genetic defect and its mechanism of action in this family could be a very important contribution to the field.

Genetics of Craniofacial Disorders:
Towards the identification of genes important for craniofacial and tooth development, we identify rare families and rare individual patients with craniofacial anomalies including cleft lip and palate, and many dental disorders. We apply positional cloning approaches to identify the underlying genetic defect and determine the mechanism of action of the mutation. Anomalies of tooth numbers such as hypodontia and supernumerary teeth constitute the most commonly encountered dental defect. We have previously identified a mutation in PAX9 in a family with hypodontia involving molars. We have identified additional families segregating specific classes of non-syndromic hypodontia of unknown etiology, of non-syndromic supernumerary teeth, and other rare dental anomalies and seek to identify the underlying gene(s) by genome-wide linkage analysis, candidate gene identification and mutation analysis. We are also studying rare individual patients using genomics approaches to decipher the critical gene underlying the congenital anomaly.

Genetics of Asian Indians:
Although the prevalence of complex genetic diseases in Asian Indians, particularly coronary artery disease(CAD) is very high, these populations have not been incorporated in any large-scale genomic surveys. Knowledge of population structure is important in disease gene association studies to avoid false associations that can be produced by heterogeneity in the ancestry of the individuals being studied. We have examined autosomal genetic variation at 1200 genome-wide polymorphic loci in a collection of 432 individuals from 15 different language groups. We found that populations from India, and those from South Asia more generally, constitute one of the major human ancestry subgroups. Surprisingly, despite their geographic and linguistic diversity, only a slight amount of genetic differentiation exists among the Indian populations compared to world populations. We are continuing to examine endogamic populations from India to determine their genetic structure and their utility for study of complex diseases.

Many independent studies have shown that the prevalence of CAD in individuals of Asian Indian origin is much higher than in other ethnic groups. The prevalence of CAD in men in New Delhi, India is four times (9.7% vs. 2.5%) that of men in the Framingham Offspring Study group. The prevalence of CAD among the ~35,000 immigrant male U.S. physicians born in India is three times (7.2% versus 2.5%) that of men in the Framingham Study. In the U.K., the overall CAD mortality in Asian Indian men is 50% higher than the countrywide average but it is 313% higher in Asian Indian men who are < 30 years of age. We are interested in identifying genetic factors that underlie the increased predisposition to CAD in Asian Indians.