B.A., New York University, 1979
Ph.D., New York University, 1984
M.D., New York University School of Medicine, 1985
Postdoc, New York University, 1986
Resident in Pediatrics, Baylor College of Medicine, 1989
Fellow in Medical Genetics, Baylor College of Medicine, 1991
Sabbatical, Sanger Centre, Cambridge, United Kingdom, 2005

RESEARCH INTERESTS:
To what extent are de novo DNA rearrangements in the human genome responsible for sporadic human traits including birth defects? How many human Mendelian and complex traits are due to structural changes and/or gene copy number variation (CNV)? What are the molecular mechanisms for human genomic rearrangements? The answers to these questions will impact both prenatal and postnatal genetic diagnostics, as well as patient management and therapeutics.

For five decades, the molecular basis of disease has been addressed in the context of how mutations effect the structure, function, or regulation of a gene or its protein product. However, we have been living in a genocentric world. During the last decade it has become apparent that many disease traits are best explained on the basis of genomic alterations. Furthermore, it has become abundantly clear that architectural features of the human genome can result in genomic instability and susceptibility to DNA rearrangements that cause disease traits – I have referred to such conditions as genomic disorders.

Fifteen years ago, it became evident that genomic rearrangements and gene dosage effects, rather than the classical model of coding region DNA sequence alterations, could be responsible for a common, autosomal dominant, adult-onset neurodegenerative trait—Charcot-Marie-Tooth neuropathy type 1A (CMT1A). With the identification of the CMT1A duplication and its reciprocal deletion causing hereditary neuropathy with liability to pressure palsies (HNPP), the demonstration that PMP22 copy-number variation (CNV) could cause inherited disease in the absence of coding-sequence alterations, was initially hard to fathom. How could such subtle changes—three copies of the normal “wild-type” PMP22 gene rather than the usual two—underlie neurologic disease?

Nevertheless, it has become apparent during this last decade and a half that neurodegeneration can represent the outcome of subtle mutations acting over prolonged time periods in tissues that do not generally regenerate, regardless of the exact molecular mechanism. This concept has revealed itself through 1) conformational changes causing prion disease, 2) the inability to degrade accumulated toxic proteins in amyloidopathies, α-synucleinopathies, and polyglutamine expansion disorders, and 3) alteration in gene copy number and/or expression levels through mechanisms such as uniparental disomy (UPD), chromosomal aberrations (e.g., translocations), and submicroscopic genomic rearrangements including duplications, deletions, and inversions.

Currently, structural variation of the human genome is commanding a great deal of attention. In the postgenomic era, the availability of human genome sequence for genome-wide analysis has revealed higher-order architectural features (i.e., beyond primary sequence information) that may cause genomic instability and susceptibility to genomic rearrangements. Nevertheless, it is perhaps less generally appreciated that any two humans contain more base-pair differences due to structural variation of the genome than resulting from single-nucleotide polymorphisms (SNPs). De novo genomic rearrangements have been shown to cause both chromosomal and Mendelian disease, as well as sporadic traits, but our understanding of the extent to which genomic rearrangements, gene CNV, and/or gene dosage alterations are responsible for common and complex neurological traits including sporadic traits remains rudimentary.

It is not clear to what extent genomic changes are responsible for disease traits, common traits (including behavioral traits), or perhaps sometimes represent benign polymorphic variation. Only recently has the ubiquitous nature of structural variation of the human genome been revealed. Central to our understanding of human biology, evolution, and disease is an answer to the following questions: What is the frequency of de novo structural genomic changes in the human genome? and What are the molecular mechanisms for genomic rearrangements?

Back to top

SELECTED PUBLICATIONS:
1. Tobin JL, Di Franco M, Eichers E, May-Simera H, Garcia M, Yan J, Justice M, Quinlan R, Justice MJ, Hennekam R, Briscoe J, Tada M, Mayor R, Burns A, Lupski JR, Hammond P, Beales PL (2008). Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung’s disease in Bardet-Biedl syndrome. Proc. Natl. Acad. Sci. USA. 105: 6714-6719.

2. Lee J, Carvalho CMB, Lupski JR (2007). A DNA replication mechanism for generating non-recurrent rearrangements associated with genomic disorders. Cell 131: 1235-1247.

3. Lupski JR (2007). Genomic rearrangements and sporadic disease. Nat. Genet. 39: S43-S47

4. Chow CY, Zhang Y, Adamska M, Dowling J, Shiga K, Szigeti K, Shy M, Lupski JR, Weisman L, Meisler MH (2007). Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and in patients with CMT4J. Nature 448: 68-72.

5. Khajavi M, Shiga K, Wiszniewski W, He F, Yan J, Wensel T, Snipes GJ, Lupski JR (2007). Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: A potential therapy for inherited neuropathy. Am. J. Hum. Genet. 81: 438-453.

6. Lupski JR (2007). Structural variation in the human genome. N. Engl. J. Med. 356: 1169-1171.

7. Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski JR (2007). Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80: 633-649.

8. Genomic Disorders – The Genomic Basis of Disease (2006). Lupski JR and Stankiewicz P (Eds.) Humana Press, Totowa, NJ pp. 1-427.

9. Walz K, Paylor R, Yan J, Bi W, Lupski JR (2006). Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). J. Clin. Invest. 116: 3035-3041.

10. El-Khamisy SF, Saifi MG, Ju L, Nash HA, Weinfeld M, Lupski JR, Caldecott KW (2005). Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434: 108-113.

11. Inoue K, Khajavi M, Ohyama T, Hirabayashi S, Wilson J, Reggin JD, Mancias P, Butler IJ, Wilkinson MF, Wegner M, Lupski JR (2004). Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet. 36: 361-369.

12. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR (2001). Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293: 2256-2259.

For more publications, see listing on Pub Med.

Back to top

CLINICAL INFORMATION:
Board Certifications:
American Board of Medical Genetics: Clinical Genetics, Clinical Molecular Genetics; Fellow of the American College of Medical Genetics: 1994-present

Primary Focus:
Determine the molecular mechanisms for disease using human genetic approaches to investigate clinical phenotypes.

Professional Organizations:
Member, Institute of Medicine, National Academies of Science (Elected 2002)
Member, American Society for Clinical Investigation (Elected 1998)
Member, American Association for the Advancement of Science (Elected Fellow 1996)
Member, Society for Pediatric Research (Elected 1992)
Member, Genetics Society of America
Member, American Society of Human Genetics
Member, American Society for Microbiology
Member, American Academy of Pediatrics
Member, American Federation for Medical Research
Member, Harris County Hospital Society
Member, Texas Medical Association
Member, Southern Medical Association
Member, American Medical Association

Back to top

CONTACT INFORMATION:
James R. Lupski, M.D., Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, 604B
Houston, Texas 77030, U.S.A.

Telephone: (713) 798-6530
Fax: (713) 798-5073
E-mail:

dup 17p11.2 GCRC protocol: http://www.bcm.edu/genetics/dup17p11.2/

Back to top

Last Modified: 6/2008