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Educational Background:
Dr. Patel received her Ph.D. in Biochemistry in 1982 from West Virginia University and did her Postdoctoral Training in human molecular genetics at Baylor College of Medicine. Prior to joining the Institute for Genetic Medicine in 2004, Dr. Patel was a Professor of Neurology, Molecular and Human Genetics, and Neuroscience at Baylor College of Medicine.
Research Interests:
The central theme in my laboratory is understanding the genetic basis of inherited diseases particularly those involving the craniofacial region and 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.
Selected Publications:
Gene discovery and mutational mechanisms for neurological diseases
Lupski JR, Montes de Oca-Luna R, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, Saucedo-Cardenas O, Barker DF, Killian JM, Garcia CA, Chakravarti A and Patel PI 1991. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219-232.(Click here to download PDF)
Lupski JR, Wise CA, Kuwano A, Pentao L, Parke JT, Glaze DG, Ledbetter DH, Greenberg F and Patel PI 1992. Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nature Genet. 1:29-33.
Patel PI, Roa B, Welcher A, Schoener-Scott R, Trask BJ, Pentao L, Snipes GJ, Garcia CA, Francke U, Shooter E, Lupski JR and Suter U 1992. The gene for the peripheral myelin protein PMP-22 gene is a candidate for Charcot-Marie-Tooth disease type 1A Nature Genetics. 1:159-165.
Pentao L, Wise C, Chinault AC, Patel PI and Lupski JR 1992. The Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genetics 2:292-300.
Roa BB, Garcia CA, Suter U, Kulpa DA, Wise CA, Mueller J, Welcher AA, Snipes GJ, Shooter EM, Patel PI and Lupski JR 1993. Charcot-Marie-Tooth disease Type 1A associated with a spontaneous point mutation in the PMP22 gene. New Engl J Med 329:96-101.
Roa BB, Garcia CA, Pentao L, Killian JM, Trask BJ, Suter U, Jackson Snipes G, Ortiz-Lopez R, Shooter EM, Patel PI and Lupski JR 1993. Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. Nature Genetics. 5:189-194.
Juyal RC, Figuera LE, Hauge X, Elsea SH, Lupski JR, Greenberg F, Baldini A and Patel PI (1996). Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 58:998-1007.
Bidichandani SI, Ashizawa T and Patel PI. (1997) Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet repeat expansion. Am J Hum Genet 60:1251-1256.
Elsea, SH, Purandare SM, Adell RA, Juyal RC, Davis JG, Finucane B, Magenis RE and Patel PI (1997). Definition of the critical interval for Smith-Magenis syndrome. Cytogenet Cell Genet, 79:276-281.
Bidichandani SB, Ashizawa T and Patel PI (1998). The GAA triplet repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet 62:111-121.
Bidichandani SI, Purandare SM, Taylor EE, Gumin G, Machkhas H, Harati Y, Gibbs RA, Ashizawa T and Patel PI (1999) Somatic sequence variation at the Friedreich ataxia locus includes complete contraction of the expanded GAA triplet repeat, significant length variation in serially passaged lymphoblasts and enhanced mutagenesis in the flanking sequence. Hum Mol Genet. 8:2425-36.
Regulation of genes underlying inherited diseases
Rincon-Limas D, Krueger D and Patel PI 1991. Functional characterization of the human hypoxanthine phosphoribosyltransferase gene promoter: evidence for a negative regulatory element. Mol Cell Biol 11:4157-4164.
Rincon-Limas D, Geske R, Xue J-J, Hsu CY, Overbeek PA and Patel PI 1994. 5'-flanking sequences of the human HPRT gene direct neuronal expression in the brain of transgenic mice. J Neurosci Res 38:259-267.
Suter U, Snipes GJ, Schoener-Scott R, Welcher AA, Pareek S, Lupski JR, Murphy RA, Shooter EM and Patel PI 1994. Regulation of tissue-specific expression of alternative Peripheral Myelin Protein-22 (PMP22) gene transcripts by two promoters. J Biol Chem 269:25797-25808.
Rincon-Limas DE, Amaya-Manzanares F, Nino-Rosales ML, Yu Y-J, Yang TP and Patel PI 1995. Ubiquitous and neuronal DNA-binding proteins interact with a negative regulatory element of the human HPRT gene. Mol Cell Biol 15:6561-6571.
Hai M, Bidichandani S and Patel PI (2001) Identification of a positive regulatory element in the myelin-specific promoter of the human PMP22 gene. J Neurosci Res 65:508-519.
Hai M, Muja N, DeVries GH, Quarles RH and Patel PI. (2002) Comparative analysis of Schwann cell lines as model systems for myelin gene transcription studies. J Neurosci Res 4:497-508.
Gene discovery for dental diseases
Stockton DW, Das P, Goldenberg M, D'Souza RN and Patel PI (2000) Mutation of PAX9 is associated with oligodontia. Nature Genet. 24:18-9.(Click here to download PDF)
Goldenberg M, Das P, Messersmith M, Stockton DW, Patel PI and D'Souza RN (2000) Clinical, radiographic and genetic evaluation of a novel form of autosomal dominant oligodontia. J Dental Res 79:1469-1475.
Patel PI (2001) Soundbites (Invited News and Views). Nature Genetics 27:129-130.
Das P, ,Stockton DW, Bauer C, Shaffer LD, D'Souza RN, Wright JT and Patel PI (2002) Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum Genet 110:371-376.
Das P, Hai M, Elcock C, Leal SM, Brown DT, Brook AH and Patel PI. (2003) Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia. Amer J Med Genet 118:35-42.
Pemberton TJ, Gee J and Patel PI (2006) Gene discovery for dental anomalies: a primer for the dental professional. J Am Dent Assoc 137:743-752.
Tarpey P, Pemberton TJ, Stockton DW, Das P, Ninis V, Edkins S, Futreal PA, Wooster, Kamath S, Nayak R, Stratton MR and Patel PI (2007) A novel Gln358Glu mutation in the EDA gene causes X-linked dominant incisor hypodontia. Amer J Med Genet 143:390-4.
Mendoza G, Pemberton TJ, Lee K, Scarel-Caminaga R, Mehrian-Shai R, Gonzalez C, Ninis V, Hartiala J, Allayee H, Snead ML, Leal SM, Line SRP and Patel PI (2007) A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.1. Hum Genet 120:653-62.
Pemberton TJ, Li F-Y, Oka S, Mendoza-Fandino GA, Hsu Y-H, Bringas P, Chai Y, Snead ML, Mehrian-Shai R, and Patel PI (2007). Identification of novel genes expressed during mouse tooth development by microarray gene expression analysis. Dev Dyn 236:2245-.2257.
Gene mapping of unusual phenotypes
Figuera LE, Pandolfo M, Dunne PW, Cantu JM and Patel PI (1995) Mapping of the congenital generalized hypertrichosis locus to chromosome Xq24-27.1 Nature Genet. 10:202-207.
Population genetics and genetics of complex traits
Tymchuk, CN, Hartiala, J, Patel, PI, Mehrabian, M and Allayee, H. (2006) Non-conventional genetic risk factors for cardiovascular disease. Curr Atheroscler Rep 8:184-92.
Rosenberg NA, Mahajan S, Gonzales C, Nino-Rosales ML, Ninis V, Das P, Molinari L, Zapata G, Weber JL, Belmont JW and Patel PI (2006). Low levels of genetic divergence across geographically and linguistically diverse populations from India. PLoS Genet 2(12):e215.
Pemberton TJ, Mehta N, Witonsky D, Di Rienzo A, Allayee H, Conti D, and Patel PI (2008) Prevalence of common disease-associated polymorphisms in Asian Indians. BMC Genetics 9:13.
Pemberton TJ, Jakobsson M, Conrad DF, Coop G, Wall JD, Pritchard JK, Patel PI, and Rosenberg NA. (2008) Improving tag SNP portability using optimal mixtures of database samples: an analysis of haplotype variation, linkage disequilibrium, and SNP tagging in populations from India. Annals Genet 72: 535-46.
All publications from Pubmed
In the News:
Houston Chronicle, July 27, 1991
New York Times, August 6, 1991
Houston Chronicle, June 1, 1992
Science, June 9, 1995
New York Times, May 31, 1995
Washington Post, May 31, 1995
Houston Chronicle, May 31, 1995
Dallas Morning News, May 31, 1995
Texas Medical Center News, February 1, 2000
Hindustan Times, December 29, 2006
IndUS Business Journal, August 15, 2007
Philadelphia Enquirer, April 21, 2008
Alumni: Publications and Current Positions
Brunella Franco, M.D.
Diego Rincon-Limas, Ph.D.
Ramesh Juyal, Ph.D.
Luis Figuera, M.D.
Sarah Elsea, Ph.D.
Sanjay Bidichandani, MD, Ph.D.
Mehreen Hai, Ph.D.
Parimal Das, Ph.D.
Trevor Pemberton, D. Phil.
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