Vanderbilt University School of Medicine

Sutcliffe, James S. , Ph.D.
Associate Professor of Molecular Physiology and Biophysics
Associate Professor of Psychiatry

Lab Url: http://sutcliffelab.org

Phone Number: (615) 936-3626

Email Address:james.s.sutcliffe@vanderbilt.edu

Sutcliffe, James's picture

Office Address   Mailing Address

8114 MRB III

6133 MRB 3 Molecular Neuroscience 37232-8548


Research Keywords
Human Genetics, Autism Genetics, Neuropsychiatric genetics, Molecular Genetics, Statistical Genetics, Chromosome, Genetics, Genome, Genomics, Mutation, Neuroscience, Polymorphism, Major Depression,Chromosome,Gene regulation,Genetics,Genome,Genomics,Human Genetics,Molecular medicine,Mutation,Neuroscience,Pharmacology,Polymorphism,Recombination

Research Specialty
Genetic basis of autism spectrum disorders; molecular genetics; statistical genetics; epigenetics, neuropsychiatric genetics; phenotypic dissection of complex genetic disorders (autism, anxiety, major depression, obsessive-compulsive disorder, and other related conditions)

Research Description
Autism is a neurodevelopmental disorder affecting approximately 1 per 500 children. The broader autism spectrum of pervasive developmental disorders may have a current prevalene as high as 1 in 150. Autism exhibits a complex genetic etiology with significant clinical and locus heterogeneity. Alleles at up to twenty genes may combine in some unknown way to produce the overall risk for development of this disorder in any one individual or family.

Our web site on autism and ongoing studies is at http://autismgenes.org

We are dissecting the genetics of autism using a combination of molecular and statistical genetic approaches, informed by the altered physiology and neurodevelopment observed in patients. We are using state of the art methods to identify genetic effects using linkage and allelic association analyses, as well as testing for potential for gene-gene or epigenetic effects that may play a role in disease susceptibility. Additionally, we are dissecting the autism phenotype by using genetically-relevant traits that represent subphenotypes of this clinically variable disorder. Quantitative traits may be particularly useful in identifying loci that contribute to specific aspects of the phenotype rather than the phenotype overall.

Several candidate regions are the focus of ongoing study. One such interval in chromosome 15q11-q13 has been implicated in autism-spectrum phenotypes based on observations of chromosomal duplications leading to increased gene copy for this region. Potential maternal-specificity of the duplication origin and increasing severity of phenotype with increasing gene copy imply involvement of genomic imprinting and gene dosage effects. This chromosomal region harbors genes involved in two other neurobehavioral phenotypes (Prader-Willi syndrome and Angelman syndrome), which exhibit opposite patterns of genomic imprinting and features in common with autism. Candidate gene and linkage studies have yielded evidence for involvement of this region in susceptibility for development of autism in families without chromosomal abnormalities. Functional candidate genes in the relevant 15q11-q13 interval include a cluster of gamma-aminobutyric acid (GABA) receptor subunits (beta3, alpha5 and gamma3), the E6-AP ubiquitin-protein ligase (UBE3A) gene, also responsible for Angelman syndrome. This region is also a prime candidate for involvement of some epigenetic phenomenon that will be difficult to identify using standard approaches.

Other candidate regions we are studying include chromosomes 17q11 and 19p. These and other regions were detected by genomic linkage in autism families and all contain genes which are thought to be highly relevant to the known neurobiology of autism. A notable example is the serotonin transporter gene (SLC6A4), which maps to 17q11.2 and has long been considered an excellent functional candidate gene in autism and other neuropsychiatric disorders. Finally, we are pursuing candidate genes in neuronal systems thought to be important in autism, including serotonin, glutamate, and several others. Our approach is to examine genes and intervals using a combination of genetic linkage and high-resolution allelic association studies in autism families and through direct screening for disease-specific mutations. As disease-associated alleles are identified, we will identify the specific susceptibility variant and determine how it affects gene expression or protein function using various in vitro and in vivo (e.g. mouse models) strategies.

Publications
Sutcliffe, JS. Affiliative behaviors and beyond: it''s the phenotype, stupid. Biol Psychiatry, 63(10), 909-10, 2008.

Sutcliffe, JS. Genetics. Insights into the pathogenesis of autism. Science, 321(5886), 208-9, 2008.

Autism Genome Project Consortium (JS Sutcliffe and others):. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. ,. Nat Genet, 39, 319-328, 2007.

Campbell, DB, Sutcliffe, JS, Ebert, PJ, Militerni, R, Bravaccio, C, Trillo, S, Elia, M, Schneider, C, Melmed, R, Sacco, R, Persico, AM, Levitt, P. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A, 103(45), 16834-9, 2006. PMCID:1838551

Ma, S, Abou-Khalil, B, Blair, MA, Sutcliffe, JS, Haines, JL, Hedera, P. Mutations in GABRA1, GABRA5, GABRG2 and GABRD receptor genes are not a major factor in the pathogenesis of familial focal epilepsy preceded by febrile seizures. Neurosci Lett, 394(1), 74-8, 2006.

Rabionet K, McCauley JL, Jawarski JM, Ashley-Kock AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA:. No association between autism and SLC25A12. . Am J Psychiatry, 163, 929-31, 2006.

Weiss LA, Kosova G, Delahanty RJ, Jiang L, Cook Jr EH, Ober C and Sutcliffe JS. Variation in ITGB3 is associated with whole blood serotonin level and autism susceptibility. Eur J Hum Genet, in press, , 2006.

Ma, S, Abou-Khalil, B, Sutcliffe, JS, Haines, JL, Hedera, P. The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures. BMC Med Genet, 6, 13, 2005. PMCID:1079842

McCauley JL, Li C, Jiang L, Olson LM, Crockett G, Gainer K, Folstein SE, Haines JL, Sutcliffe JS:. Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates.. BMC Med Genet, 6(1), 1, 2005.

McCauley, JL, Li, C, Jiang, L, Olson, LM, Crockett, G, Gainer, K, Folstein, SE, Haines, JL, Sutcliffe, JS. Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet, 6, 1, 2005. PMCID:546213

Prasad HC, Zhu C-B, McCauley JL, Shelton R, Hewlett WA, Sutcliffe JS and Blakely RD: . Human serotonin transporter coding variants display selective insensitivity to Protein Kinase G and p38 Mitogen Activated Protein Kinase. . Proc Natl Acad Sci USA,, 102(32), 11545-11550, 2005.

Prasad, HC, Zhu, CB, McCauley, JL, Samuvel, DJ, Ramamoorthy, S, Shelton, RC, Hewlett, WA, Sutcliffe, JS, Blakely, RD. Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A, , , 2005. PMCID:1183547

Sutcliffe, JS, Delahanty, RJ, Prasad, HC, McCauley, JL, Han, Q, Jiang, L, Li, C, Folstein, SE, Blakely, RD. Allelic Heterogeneity at the Serotonin Transporter Locus (SLC6A4) Confers Susceptibility to Autism and Rigid-Compulsive Behaviors. Am J Hum Genet, 77(2), 265-79, 2005. PMCID:1224529

Dykens, Elisabeth M, Sutcliffe, James S, Levitt, Pat. Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues. Ment Retard Dev Disabil Res Rev, 10(4), 284-91, 2004.

Hedera, Peter, Abou-Khalil, Bassel, Crunk, Amy E, Taylor, Kelly A, Haines, Jonathan L, Sutcliffe, James S. Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene. Epilepsia, 45(3), 218-22, 2004.

Hutcheson, Holli, Olson, Lana, Bradford, Yuki, Folstein, Susan, Santangelo, Susan, Sutcliffe, James, Haines, Jonathan. Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes. BMC Med Genet, 5(1), 12, 2004. PMCID:420465

McCauley JL, Olson LM, Amin T, Organ EL, Folstein SE, Haines JL and Sutcliffe JS:. A linkage disequilibrium map of the 1-Mb 15q12 GABAA receptor subunit cluster and association to autism. . Am J Med Genet (B), 131(B), 55-59, 2004.

McCauley, J L, Olson, L M, Dowd, M, Amin, T, Steele, A, Blakely, R D, Folstein, S E, Haines, J L, Sutcliffe, J S. Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism. Am J Med Genet, 127B(1), 104-12, 2004.

McCauley, JL, Olson, LM, Delahanty, R, Amin, T, Nurmi, EL, Organ, EL, Jacobs, MM, Folstein, SE, Haines, JL, Sutcliffe, JS. A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet, 131(1), 51-9, 2004.

Rabionet, Raquel, Jaworski, James M, Ashley-Koch, Allison E, Martin, Eden R, Sutcliffe, James S, Haines, Jonathan L, Delong, G Robert, Abramson, Ruth K, Wright, Harry H, Cuccaro, Michael L, Gilbert, John R, Pericak-Vance, Margaret A. Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes. Neurosci Lett, 372(3), 209-14, 2004.

Skaar, D A, Shao, Y, Haines, J L, Stenger, J E, Jaworski, J, Martin, E R, Delong, G R, Moore, J H, McCauley, J L, Sutcliffe, J S, Ashley-Koch, A E, Cuccaro, M L, Folstein, S E, Gilbert, J R, Pericak-Vance, M A. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry, , , 2004.

Hutcheson, Holli B, Bradford, Y, Folstein, S E, Gardiner, M B, Santangelo, S L, Sutcliffe, J S, Haines, J L. Defining the autism minimum candidate gene region on chromosome 7. Am J Med Genet, 117B, 90-6, 2003.

Matsumura, M, Kubota, T, Hidaka, E, Wakui, K, Kadowaki, S, Ueta, I, Shimizu, T, Ueno, I, Yamauchi, K, Herzing, L B, Nurmi, E L, Sutcliffe, J S, Fukushima, Y, Katsuyama, T. ''Severe'' Prader-Willi syndrome with a large deletion of chromosome 15 due to an unbalanced t(15,22)(q14;q11.2) translocation. Clin Genet, 63(1), 79-81, 2003.

Nurmi, E L, Amin, T, Olson, L M, Jacobs, M M, McCauley, J L, Lam, A Y, Organ, E L, Folstein, S E, Haines, J L, Sutcliffe, J S. Dense linkage disequilibrium mapping in the 15q11-q13 maternal expression domain yields evidence for association in autism. Mol Psychiatry, 8, 624-34, 2003.

Nurmi, Erika L, Dowd, Michael, Tadevosyan-Leyfer, Ovsanna, Haines, Jonathan L, Folstein, Susan E, Sutcliffe, James S. Exploratory subsetting of Autism families based on savant skills improves evidence of genetic linkage to 15q11-q13. J Am Acad Child Adolesc Psychiatry, 42, 856-63, 2003.

Sutcliffe, James S, Han, Michael K, Amin, Taneem, Kesterson, Robert A, Nurmi, Erika L. Partial duplication of the APBA2 gene in chromosome 15q13 corresponds to duplicon structures. BMC Genomics, 4, 15, 2003. PMCID:156605

Sutcliffe, James S, Nurmi, Erika L, Lombroso, Paul J. Genetics of childhood disorders: XLVII. Autism, part 6: duplication and inherited susceptibility of chromosome 15q11-q13 genes in autism. J Am Acad Child Adolesc Psychiatry, 42(2), 253-6, 2003.

Abou-Khalil, B, Ge, Q, Desai, R, Ryther, R, Bazyk, A, Bailey, R, Haines, J L, Sutcliffe, J S, George, A L. Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. Neurology, 57(12), 2265-72, 2001.

Joseph, B, Egli, M, Sutcliffe, J S, Thompson, T. Possible dosage effect of maternally expressed genes on visual recognition memory in Prader-Willi syndrome. Am J Med Genet, 105(1), 71-5, 2001.

Nurmi, E L, Bradford, Y, Chen, Y, Hall, J, Arnone, B, Gardiner, M B, Hutcheson, H B, Gilbert, J R, Pericak-Vance, M A, Copeland-Yates, S A, Michaelis, R C, Wassink, T H, Santangelo, S L, Sheffield, V C, Piven, J, Folstein, S E, Haines, J L, Sutcliffe, J S. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics, 77(1-2), 105-13, 2001.

Dimitropoulos, A, Feurer, ID, Roof, E, Stone, W, Butler, MG, Sutcliffe, J, Thompson, T. Appetitive behavior, compulsivity, and neurochemistry in Prader-Willi syndrome. Ment Retard Dev Disabil Res Rev, 6(2), 125-30, 2000.

Fang, P, Lev-Lehman, E, Tsai, T F, Matsuura, T, Benton, C S, Sutcliffe, J S, Christian, S L, Kubota, T, Halley, D J, Meijers-Heijboer, H, Langlois, S, Graham, J M, Beuten, J, Willems, P J, Ledbetter, D H, Beaudet, A L. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet, 8(1), 129-35, 1999.

Christian, S L, Bhatt, N K, Martin, S A, Sutcliffe, J S, Kubota, T, Huang, B, Mutirangura, A, Chinault, A C, Beaudet, A L, Ledbetter, D H. Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb. Genome Res, 8(2), 146-57, 1998. PMCID:310691

Albrecht, U, Sutcliffe, J S, Cattanach, B M, Beechey, C V, Armstrong, D, Eichele, G, Beaudet, A L. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet, 17(1), 75-8, 1997.

Huq, A H, Sutcliffe, J S, Nakao, M, Shen, Y, Gibbs, R A, Beaudet, A L. Sequencing and functional analysis of the SNRPN promoter: in vitro methylation abolishes promoter activity. Genome Res, 7(6), 642-8, 1997. PMCID:310659

Matsuura, T, Sutcliffe, J S, Fang, P, Galjaard, R J, Jiang, Y H, Benton, C S, Rommens, J M, Beaudet, A L. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet, 15(1), 74-7, 1997.

Sutcliffe, J S, Han, M, Christian, S L, Ledbetter, D H. Neuronally-expressed necdin gene: an imprinted candidate gene in Prader-Willi syndrome. Lancet, 350(9090), 1520-1, 1997.

Sutcliffe, J S, Jiang, Y H, Galijaard, R J, Matsuura, T, Fang, P, Kubota, T, Christian, S L, Bressler, J, Cattanach, B, Ledbetter, D H, Beaudet, A L. The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res, 7(4), 368-77, 1997. PMCID:139148

Beuten, J, Hennekam, R C, Van Roy, B, Mangelschots, K, Sutcliffe, J S, Halley, D J, Hennekam, F A, Beaudet, A L, Willems, P J. Angelman syndrome in an inbred family. Hum Genet, 97(3), 294-8, 1996.

Beuten, J, Sutcliffe, J S, Casey, B M, Beaudet, A L, Hennekam, R C, Willems, P J. Detection of imprinting mutations in Angelman syndrome using a probe for exon alpha of SNRPN. Am J Med Genet, 63(2), 414-5, 1996.

Jinno, Y, Sengoku, K, Nakao, M, Tamate, K, Miyamoto, T, Matsuzaka, T, Sutcliffe, J S, Anan, T, Takuma, N, Nishiwaki, K, Ikeda, Y, Ishimaru, T, Ishikawa, M, Niikawa, N. Mouse/human sequence divergence in a region with a paternal-specific methylation imprint at the human H19 locus. Hum Mol Genet, 5(8), 1155-61, 1996.

Kubota, T, Sutcliffe, J S, Aradhya, S, Gillessen-Kaesbach, G, Christian, S L, Horsthemke, B, Beaudet, A L, Ledbetter, D H. Validation studies of SNRPN methylation as a diagnostic test for Prader-Willi syndrome. Am J Med Genet, 66(1), 77-80, 1996.

Nakao, M, Sutcliffe, J S, Beaudet, A L. Advantages of RT-PCR and denaturing gradient gel electrophoresis for analysis of genomic imprinting: detection of new mouse and human expressed polymorphisms. Hum Mutat, 7(2), 144-8, 1996.

Ning, Y, Roschke, A, Christian, S L, Lesser, J, Sutcliffe, J S, Ledbetter, D H. Identification of a novel paternally expressed transcript adjacent to snRPN in the Prader-Willi syndrome critical region. Genome Res, 6(8), 742-6, 1996.

Gunaratne, P H, Nakao, M, Ledbetter, D H, Sutcliffe, J S, Chinault, A C. Tissue-specific and allele-specific replication timing control in the imprinted human Prader-Willi syndrome region. Genes Dev, 9(7), 808-20, 1995.

Nakao, M, Sutcliffe, J S, Durtschi, B, Mutirangura, A, Ledbetter, D H, Beaudet, A L. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum Mol Genet, 3(2), 309-15, 1994.

Sutcliffe, J S, Nakao, M, Christian, S, Orstavik, K H, Tommerup, N, Ledbetter, D H, Beaudet, A L. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet, 8(1), 52-8, 1994.

Ashley, C T, Sutcliffe, J S, Kunst, C B, Leiner, H A, Eichler, E E, Nelson, D L, Warren, S T. Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat. Nat Genet, 4(3), 244-51, 1993.

Hinds, H L, Ashley, C T, Sutcliffe, J S, Nelson, D L, Warren, S T, Housman, D E, Schalling, M. Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat Genet, 3(1), 36-43, 1993.

Mutirangura, A, Jayakumar, A, Sutcliffe, J S, Nakao, M, McKinney, M J, Buiting, K, Horsthemke, B, Beaudet, A L, Chinault, A C, Ledbetter, D H. A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11-q13) and refined localization of the SNRPN gene. Genomics, 18(3), 546-52, 1993.

Riggins, G J, Sherman, S L, Oostra, B A, Sutcliffe, J S, Feitell, D, Nelson, D L, van Oost, B A, Smits, A P, Ramos, F J, Pfendner, E. Characterization of a highly polymorphic dinucleotide repeat 150 KB proximal to the fragile X site. Am J Med Genet, 43(1-2), 237-43, 1992.

Sutcliffe, J S, Nelson, D L, Zhang, F, Pieretti, M, Caskey, C T, Saxe, D, Warren, S T. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet, 1(6), 397-400, 1992.

Sutcliffe, J S, Zhang, F, Caskey, C T, Nelson, D L, Warren, S T. PCR amplification and analysis of yeast artificial chromosomes. Genomics, 13(4), 1303-6, 1992.

Fu, Y H, Kuhl, D P, Pizzuti, A, Pieretti, M, Sutcliffe, J S, Richards, S, Verkerk, A J, Holden, J J, Fenwick, R G, Warren, S T. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell, 67(6), 1047-58, 1991.

Robinson, MJ, Martin, BA, Gootz, TD, McGuirk, PR, Moynihan, M, Sutcliffe, JA, Osheroff, N. Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage. J Biol Chem, 266(22), 14585-92, 1991.

Verkerk, A J, Pieretti, M, Sutcliffe, J S, Fu, Y H, Kuhl, D P, Pizzuti, A, Reiner, O, Richards, S, Victoria, M F, Zhang, F P. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell, 65(5), 905-14, 1991.

Warren, S T, Zhang, F P, Sutcliffe, J S, Peters, J F. Strategy for molecular cloning of the fragile X site DNA. Am J Med Genet, 30(1-2), 613-23, 1988.


Postdoctoral Position Available
Yes

Postdoctoral Position Details
The focus of this position is on the study of complex human neuropsychiatric diseases, particularly autism spectrum disorders. A combination of advanced molecular and statistical genetic methods are being applied to identify genes, and in particular susceptibility or risk-associated alleles at these genes, to identify loci of main effect as well as those which may exhibit gene-gene or allelic interaction with loci elsewhere in the genome. While our current focus is on autism, a pending grant application relates to the pharmacogenetics of major depression. This position entails interaction between investigators, students and post-docs in the fields of molecular and statistical genetics, neuroscience, and clinicians or clinical (or phenotype-oriented) researchers to develop methods to relate trait-based subsets of complex phenotypes like autism and depression to their ultimate genotype-phenotype relationships.

Postdoctoral applicants should be eligible for NIH trainiing grant support

Updated Date
01/22/2013



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