Anand K. Srivastava, PhD
Associate Director - Center for Molecular Studies
Senior Research Scientist
The research interest of my group is to understand the etiology of inherited developmental disorders of the central nervous system (brain development and function) and epithelial organogenesis. As entry points to two major classes of process, we have been starting from favorable patient material, using targeted cloning to isolate "disease genes" and adding cell biology and transgenic approaches to elucidate gene function.
Brain development and function: Our approach is to identify and characterize specific genes associated with developmental brain disorders of three types: leading to intellectual disability (ID); affecting corticogenesis (Lissencephaly); or associated with aberrant behavior (Smith-Magenis syndrome, Autism). Intellectual disability is the most common developmental disability, affecting intellectual and adaptive functions in approximately 2-3% of the population, yet the underlying cause of ID is established in less than half of all cases. The long-term goals of our research are to increase the understanding of genes and genetic pathways involved in brain development and cognitive and adaptive functions and to improve diagnosis of the genetic pathology in large numbers of male and female ID patients. We have delineated several potential autosomal and X-linked ID loci by analyzing patients with ID and balanced chromosome rearrangements (X;autosome and autosome;autosome translocations; chromosome inversions and deletions). Using balanced chromosome translocations, we have cloned the gene, DCX, responsible for X-linked lissencephaly/subcortical band heterotopia (LISX/SBH) and the AGTR2 gene, responsible for X-linked ID.
Epithelial appendage formation: Ectodermal dysplasias (EDs) comprise a large group of syndromes involving defective development of hair follicles, sweat glands, teeth and nails. We have identified and characterized the gene responsible for the X-linked anhidrotic ectodermal dysplasia (EDA), the most common ED, and its mouse counterpart, Tabby (Ta). These genes encode isoforms of a membrane-associated collagenous proteins, ectodysplasin-A. Recently, we have shown that the expression of the ectodysplasian-A1 isoform in Tabby males resulted in restored hair growth, dermal ridges, and sweat glands as well as positive effect on tooth development. Our data provide the first direct physiological evidence that EDA-A1 is a key regulator of hair follicle and sweat gland initiation; its soluble ligand form could aid in deriving therapeutic reagents for conditions affecting hair and sweat gland formation. We are also exploring how the EDA/Ta gene functions in the gene networks regulating early morphogenesis of skin appendages.
Vieira GH, Rodriguez JD, Carmona-Mora P, Cao L, Gamba BF, Carvalho DR, de Rezende Duarte A, Santos SR, de Souza DH, Dupont BR, Walz K, Moretti-Ferreira D, Srivastava AK. Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome. Eur J Hum Genet. 2011 Sep 7. [Epub ahead of print]
Dukes-Rimsky L, Guzauskas GF, Holden KR, Griggs R, Ladd S, Del Carmen Montoya M, Dupont BR, Srivastava AK. Microdeletion at 4q21.3 is associated with intellectual disability, dysmorphic facies, hypotonia, and short stature. Am J Med Genet A. 2011 Sep;155(9):2146-53.
Vieira GH, Rodriguez JD, Boy R, de Paiva IS, DuPont BR, Moretti-Ferreira D, Srivastava AK. Differential diagnosis of Smith-Magenis syndrome: 1p36 deletion syndrome. Am J Med Genet A. 2011 May;155A(5):988-92.
Teng S, Srivastava AK, Schwartz CE, Alexov E, Wang L. Structural assessment of the effects of amino acid substitutions on protein stability and protein-protein interaction. Int J Comput Biol Drug Des. 2011;3(4):334-49.
Wang L, Srivastava AK, Schwartz CE. Microarray data integration for genome wide analysis of human tissue-selective gene expression. BMC Genomics, 11 Suppl 2: S15, P1-10, 2010.
Teng S, Srivastava AK, Wang L. Sequence feature-based prediction of protein stability changes upon amino acid substitutions. BMC Genomics, 11 Suppl 2: S5, P1-8, 2010.
Rodriguez JD, Bhat SS, Meloni I, Ladd S, Leslie ND, Doyne EO, Renieri A, DuPont BR, Stevenson RE, Schwartz CE, Srivastava AK. Intellectual disability, midface hypoplasia, facial hypotonia and Alport syndrome are associated with a deletion in Xq22.3. Am J Med Genet A 152A: 713-717, 2010.
Pawlowski TL, Heringer-Walther S, Cheng CH, Archie JG, Chen CF, Walther T, Srivastava AK. Candidate Agtr2 influenced genes and pathways identified by expression profiling in the developing brain of Agtr2(-/y) mice. Genomics 94: 188-195, 2009.
Mues GI, Griggs R, Hartung AJ, Whelan G, Best LG, Srivastava AK*, D'Souza R*. From ectodermal dysplasia to selective tooth agenesis. Am J Med Genet A 149A: 2037-2041, 2009.
Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray C, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer APM, van Bokhoven H, Esch HV, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton M. A systematic, large-scale resequencing screen of the X chromosome coding exons in mental retardation. Nat Genet 41: 535-543, 2009.
Griggs BL, Ladd S, Decker A, DuPont BR, Asamoah A, Srivastava AK. Identification of ectodysplasin-A receptor gene deletion at 2q12.2 and a potential autosomal MR locus. Eur J Hum Genet 17: 30-36, 2009.
Bhalla K, Luo Y, Buchan T, Beachem MA, Guzauskas GF, Ladd S, Bratcher SJ, Schroer RJ, Balsamo J, DuPont BR, Lilien J, Srivastava AK. Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am J Hum Genet 83: 703-713, 2008.
Gregory ML, Guzauskas GF, Edgar TS, Clarkson KB, Srivastava AK, Holden KR. A novel GLRA1 mutation associated with an atypical hyperekplexia phenotype. J of Child Neurol 23: 1433-1438, 2008.
Cho G, Bhat SS, Gao J, Collins JS, Rogers RC, Simensen RJ, Schwartz CE, Golden JA, Srivastava AK. Evidence that SIZN1 is a candidate X-linked mental retardation gene. Am J Med Genet A 146A: 2644-2650, 2008.
Vincent JB, Choufani S, Horike S, Stachowiak B, Li M, Dill FJ, Marshall C, Hrynchak M, Pewsey E, Ukadike KC, Friedman JM, Srivastava AK, Scherer SW. A translocation t(6;7)(p11-p12;q22) associated with autism and mental retardation: localization and identification of candidate genes at the breakpoints. Psychiatric Genetics 18: 101-109, 2008.
- Bhat SS, Ladd S, Grass F, Spence JE, Brasington CK, Simensen RJ, Schwartz CE, DuPont, BR, Stevenson RE, Srivastava AK. Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism. Clinical Genet 73: 94-96, 2008.
- Griggs BL, Ladd S, Saul RA, DuPont BR, Srivastava AK. Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 91:195-202, 2008.
- Harvey CG, Menon SD, Stachowiak B, Noor A, Proctor A, Mensah AK, Mnatzakanian GN, Alfred SE, Guo R, Scherer SW, Kennedy JL, Roberts W, Srivastava AK, Minassian BA, Vincent JB. Sequence variants within exon 1 of MECP2 occur in females with mental retardation. Am J Med Genet B Neuropsychiatr Genet 144: 355-360, 2007.
- Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M: Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet 80: 345-352, 2007.
- Guzauskas GF, Ukadike K, Lynn Rimsky L, Srivastava AK. tSNP-based identification of allelic-loss of gene expression in a patient with a balanced chromosomal rearrangement. Genomics 89: 562-565, 2007.
- Tarpey PS, Raymond FL*, Nguyen LS*, Rodriguez J*, Hackett A, Vandeleur L, Smith R, Shoubridge C, Edkins S, Stevens C, O'Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Hills K, Jones D, Mironenko T, Perry J, Varian J, West S, Widaa S, Teague J, Dicks E, Butler A, Menzies A, Richardson D, Jenkinson A, Shepherd R, Raine K, Moon J, Luo Y, Parnau J, Bhat SS, Gardner A, Corbett M, Brooks D, Thomas P, Parkinson-Lawrence E, Porteous ME, Warner JP, Sanderson T, Pearson P, Simensen RJ, Skinner C, Hoganson G, Superneau D, Wooster R, Bobrow M, Turner G, Stevenson RE, Schwartz CE, Futreal PA, Srivastava AK, Stratton MR, Gécz J. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 39:1127-1133, 2007.
- Wu Y, Arai AC, Rumbaugh G, Srivastava AK, Turner G, Hayashi T, Suzuki E, Jiang Y, Zhang L, Rodriguez J, Boyle J, Tarpey P, Raymond FL, Nevelsteen J, Froyen G, Stratton M, Futreal A, Gecz J, Stevenson R, Schwartz CE, Valle D, Huganir RL, Wang T. Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc Natl Acad Sci USA 104:18163-18168, 2007.
- Vajsar J, Zhang W, Dobyns WB, Biggar D, Holden KR, Hawkins C, Ray P, Olney AH, Burson CM, Srivastava AK, Schachter H. Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts. Neuromuscul Disord 16:132-136, 2006.
- Dodds JA, Srivastava AK, Holden KR. Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis. J Child Neurol 21:331-333, 2006.
- Addison PK, Berry V, Holden KR, Espinal D, Rivera B, Su H, Srivastava AK, Bhattacharya SS. A novel mutation in the connexin 46 gene (GJA3) causes autosomal dominant zonular pulverulent cataract in a Hispanic family. Mol Vis 12:791-795, 2006.
- Bhat SS, Schmidt KR, Ladd S, Kim KC, Schwartz CE, Simensen RJ, DuPont BR, Stevenson RE, Srivastava AK. Disruption of DMD and deletion of ACSL4 causing developmental delay, hypotonia, and multiple congenital anomalies. Cytogenet Genome Res 112:170-175, 2006.
- Bhat SS, Rogers RC, Holden KR, Srivastava AK. A novel in-frame deletion in ARX is associated with lissencephaly with absent corpus callosum and hypoplastic genitalia. Am J Med Genet 138:70-72, 2005.
- Vervoort VS, Holden KR, Ukadike KC, Collins JS, Saul RA, Srivastava AK. POMGnT1 gene alterations in a family with neurological abnormalities. Ann Neurol 56:143-148, 2004.
- Cui C-Y, Durmowicz M, Ottolenghi C, Hashimoto T, Griggs B, Srivastava AK, Schlessinger D. Inducible mEDA-A1 transgene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles. Hum Mol Genet 12:2931-2940, 2003.
- Vervoort VS*, Beachem MA*, Edwards PE*, Ladd S, Miller KE, de Mollerat X, Clarkson K, DuPont B, Schwartz CE, Stevenson RE, Boyd E, Srivastava AK. AGTR2 mutations in X-linked mental retardation. Science 296:2401-2403, 2002. *Contributed equally (See also Supporting Online Material at: www.sciencemag.org/cgi/content/full/296/5577/2401/DC1)
- Cui C-Y, Durmowicz MC, Tanaka TS, Hartung AJ, Tezuka T, Hashimoto K, Ko MSH, Srivastava AK, Schlessinger D. EDA targets revealed by skin gene expression profiles of wild-type, Tabby, and Tabby EDA-A1 transgenic mice. Hum Mol Genet 11:1763-1773, 2002.
- Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nature Genet 27:79-83, 2001.
- Srivastava AK, Durmowicz MC, Hartung AJ, Hudson J, Ouzts LV, Donovan DM, Cui C-Y, Schlessinger D. Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice. Hum Mol Genet 10:2973-2981, 2001.
- Srivastava AK, McMillan S, Jermak C, Shomaker M, Copeland-Yates S, Sossey-Alaoui K, Mumm S, Schlessinger D, Nagaraja R. Integrated STS/YAC physical, genetic and transcript map of human Xq21.3 to q23/q24 (DXS1203-DXS1059). Genomics 58:188-201, 1999.
- Sossey-Alaoui K, Lyon JA, Jones L, Abidi FE, Hartung AJ, Hane B, Schwartz CE, Stevenson RE, Srivastava AK. Molecular cloning and characterization of TRPC5 (HTRP5), the human homologue of a mouse brain receptor-activated capacitative Ca2+ entry channel. Genomics 60:330-340, 1999.
- Sossey-Alaoui K, Hartung AJ, Guerrini R, Manchester DK, Posar A, Puche-Mira A, Andermann E, Dobyns WB, Srivastava AK. Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects. Hum Mol Genet 7:1327-1332, 1998.
- Bayes M, Hartung AJ, Ezer S, Pispa J, Thesleff I, Srivastava AK*, Kere J*. The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. Hum Mol Genet 7:1661-1669, 1998. *Contributed equally
- Nagaraja R. et al. X Chromosome map at 75 kb STS resolution, revealing extremes of recombination and GC content. Genome Research 7:210-222, 1997.
- Ross ME*, Allen KM*, Srivastava AK*, Featherstone T, Gleeson JG, Hirsh B, Harding BN, Andermann E, Abdullah R et al. Linkage and physical mapping of X-linked Lissencephaly/SBH (XLIS): A novel gene causing neuronal migration defects in human brain. Hum Mol Genet 6:555-562, 1997. *Contributed equally
- Srivastava AK, Pispa J, Hartung AJ, Du Y, Ezer S, Jenks T, Shimada T, Pekkanen M, Mikkola ML, Ko MSH, Thesleff I, Kere J, Schlessinger D. The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains. Proc Natl Acad Sci USA 94:13069-13074, 1997.
- Srivastava AK, Montonen O, Saarialho-Kere U, Chen E, Baybayan P, Pispa J, Limon J, Schlessinger D, Kere J. Fine mapping of the EDA gene: A translocation breakpoint is associated with a CpG island that is transcribed. Am J Hum Genet 58:126-132, 1996.
- Kere J*, Srivastava AK* Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, Chen EY, Ezer S, Saarialho-Kere U, De la Chapelle A, Schlessinger D. X-linked anhidrotic (hypohydrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nature Genet 13:409-416, 1996. *Contributed equally
- Srivastava AK. PCR in sequence-tagged site (STS) content genome mapping. In "PCR technology: Current Innovations" (Griffin HG, Griffin AM eds). CRC press Inc., Boca Raton FL, pp 239-247, 1994.
- Srivastava AK, Schlessinger D. Vectors for inserting selectable markers in vector arms and human DNA inserts of yeast artificial chromosomes (YACs). Gene 103:53-59, 1991.
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- Ph.D. (Biochemistry), Banaras Hindu University, Varanasi, India, 1986/1989
- Research Associate/Postdoctoral Fellow, Washington University School of Medicine, Dept. of Mol. Microbiol., 1986-1992
- Research Instructor, Washington University School of Medicine, Dept. of Mol. Microbiol., 1992-1995
- Assistant Research Scientist, Center for Molecular Studies, JC Self Research Institute, Greenwood Genetic Center, 1995-2000
- Adjunct Assistant Professor of Biology, Clemson University, 1996-2002
- Adjunct Professor, Department of Genetics & Biochemistry, Clemson University, 2002-present
- Associate Research Scientist, Center for Molecular Studies, JC Self Research Institute of Human Genetics, Greenwood Genetic Center, 2000-2007
- Director of Scientific Affairs, Center for Molecular Studies, JC Self Research Institute of Human Genetics, Greenwood Genetic Center, 2006-present
- Senior Research Scientist, Center for Molecular Studies, JC Self Research Institute of Human Genetics, Greenwood Genetic Center, 2007-present
- Associate Director - Center for Molecular Studies, JC Self Research Institute of Human Genetics, Greenwood Genetic Center, 2009-present