Merlin G. Butler

Professor, Department of Psychiatry and Behavioral Sciences
Primary office:


Dr. Butler is engaged in the clinical genetics practice of children and adults presenting for genetics services with emphasis on genetic disorders, developmental disabilities, congenital anomalies, cytogenetic syndromes, Prader-Willi syndrome, early onset of morbid obesity and autism. His research interests include the genetics of obesity with emphasis on Prader-Willi syndrome and obesity-related disorders, autism, psychiatric and behavioral genetics, genotype-phenotype correlations and the natural history and delineation of rare and uncommon clinical genetics syndromes. He has been an active member of several professional organizations including NIH study sections, editorial boards for journals, and conducted extramurally funded research on Prader-Willi, Angelman and fragile X syndromes, the genetics of autism and obesity and delineation of genetic disorders. He has published over 400 research articles, multiple book chapters and edited several journal issues and two textbooks. The research interests encompass clinical, cytogenetic and molecular genetic studies of subjects with rare genetic disorders, dysmorphic syndromes and microdeletion syndromes along with the genetics of developmental delay, autism, obesity and alcoholism.  Specifically, the research has focused on studies of chromosome 15 including Prader-Willi syndrome (the most common genetic cause of marked obesity in humans), fragile X syndrome, Anglemen syndrome and autism.  Prader-Willi syndrome (PWS) was the first example in humans of genomic imprinting or the differential expression of genes depending on the parent of origin. The most common cause of this disorder is a paternally derived chromosome 15q11-q13 deletion (70% of patients) followed by maternal disomy 15 (both 15’s from the mother), and epimutations of the imprinting center.  Genotype/phenotype studies to date indicate that individuals with PWS and having the chromosome 15 deletion are more homogeneous in their clinical presentation, have less pigment, lower IQ scores and are more self-injurious than those with maternal disomy 15.

 

The current studies include microarray gene expression patterns and methylation status of genes/ transcripts from the chromosome 15q11-q13 region in order to establish bi-allelic (normal) or mono-allelic (imprinted) expression patterns and parent of origin bias.  These studies will identify those genes that play a role in the causation of Prader-Willi syndrome and compare with individuals having simple obesity, rare obesity- related disorders or psychiatric/cognitive/behavioral problems including autism, self-injury, intellectual disability and schizophrenia.  With means of early diagnosis and genetic diagnostic techniques, the hope is to identify patients presenting with genetic conditions at a young age which should impact on prognosis, genetic counseling and the natural history of the syndrome. Furthermore, DNA, coding and non-coding RNA (microRNAs) studies are underway with targeted messenger RNAs from structural and regulatory genes involved in the pathogenesis of obesity, autism and neurodevelopment.

 

Previous research experience and studies that relate to aberrant behaviors include plasma GABA levels in PWS; screening for the X-linked MAOA gene mutations in target groups and impact on aggression and learning problems; examining the tryptophan hydroxylase (TPH2) gene, the rate limiting enzyme in the production of serotonin, and gene polymorphism studies associated with hyperphagia, IQ and internalizing problems in PWS along with TPH2 expression with differing genetic subtypes; genetic subtype differences in neural circuitry of food motivation in PWS; refining the 22q11.2 deletion breakpoints in DiGeorge syndrome, a common cause of aberrant behavior, aggression and autism involving the COMT gene; transcranial direct current stimulation and startle response modulation studies and food motivation in PWS and obesity; and copy number variation with microarray analysis in consecutive patients with autism and/or developmental delay presenting for genetic services. Dr. Butler recently reported a new cytogenetic susceptibility region for neurological dysfunction including developmental and language delay termed the 15q11.2 BP1-BP2 microdeletion syndrome.

Selected References:

  1. Butler, M.G. & Palmer, W.G.  (1983).  Parental origin of chromosome 15 deletion in Prader-Willi syndrome.  Lancet I:1285-1286.
  2. Butler, M.G., Pratesi, R., & Vnencak-Jones, C.L.  (1995).  Molecular genetic analysis of mentally retarded males with features of the fragile X syndrome.  J. Intell. Disabil. Res. 39:544-553.
  3. Ebert, M.H., Schmidt, D.E., Thompson, T., & Butler, M.G.  (1997).  Elevated plasma gamma-amino butyric acid (GABA) levels in individuals with Prader-Willi or Angelman syndromes.  J. Neuropsych. & Clin. Neurosci. 9:75-80.
  4. Schuback, D.E., Mulligan, E.L., Sims, K.B., Tivol, E.A., Greenberg, F.D., Chang, S.F., Yang, S.L., Mau, Y.C., Shen, C.Y., Ho, M.S., Yang, N.H., Butler, M.G., Fink, S., Schwartz, C.E., Berlin, F., Breakefield, X.O., Murphy, D.L., & Hsu, Y.P.  (1999).  Screen for MAOA mutations in target human groups.  Am. J. Med. Genet. 1:25-28.
  5. Ohta, T., Gray, T., Rogan, P.K., Buiting, K., Gabriel, J.M., Saitoh, S., Muralidhar, B., Driscoll, D.J., Horsthemke, B., Butler, M.G., & Nicholls, R.D.  (1999).  Imprinting mutation mechanisms in Prader-Willi syndrome represent a new paradigm for genetic disease.  Am. J. Hum. Genet. 64:397-413.
  6. Symons, F.J., Butler, M.G., Sanders, M.D., Feurer, I.D., & Thompson, T.  (1999).  Self-Injurious behavior and Prader-Willi syndrome: Behavioral forms and body locations.  Am. J. Ment. Retard. 104(3):260-269.
  7. Dimitropoulos, A., Feurer, I.D., Roof, E., Stone, W., Butler, M.G., Sutcliffe, J., & Thompson, T.  (2000).  Appetitive behavior, compulsivity and neurochemistry in Prader-Willi syndrome.  MRDD Res. Rev. 6:125-130.
  8. Talebizadeh, A., Bittel, D.C., Miles, J.H., Takahashi, N., Wang, C.H., Kibiryeva, N., & Butler, M.G. (2002). No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD) J. Med. Genet. 39:e70(http://www.jmedgent.com/cgi/content/full/39//e70)
  9. Butler, M.G., Bittel, D.C., Kibiryeva, N., Talebizadeh Z. & Thompson, T. (2004).  Behavioral  differences among subjects with Prader-Willi syndrome and type I and type II deletions and maternal disomy.  Pediatrics 113: 565-574.
  10. Hartley, S., MacLean, W., Butler, M.G., Zarcone, J., & Thompson, T. (2005).  Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome.  Am. J. Med. Genet. 136A:140-145.
  11. Butler, M.G., Dasouki, M.J., Miles, J., Zhou, X. P., Brown, M., Talebizadeh, Z., Wang, C.H., Takahashi, T.N., Stratton, R., Pilarski, R., & Eng, C. (2005).  Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.  J. Med. Genet. 42:318-321.
  12. Talebizadeh, Z., Bittel, D.C., Veatch, O., Kibiryeva, & Butler, M.G. (2005).  Skewed X chromosome inactivation in females with autism.  J. Autism Develop. Disord. 35:675-681.
  13. Holsen, L.M., Zarcone, J.R., Brooks, W.M., Butler, M.G., Thompson, T.I., Ahluwalia, J.S., Nollen, N.G., & Savage, C.R. (2006).  Neural mechanisms underlying hyperphagia in Prader-Willi syndrome.  Obesity 14:1028-1037.
  14. Talebizadeh, Z., Lam, D.Y., Theodoro, M.F., Bittel, D.C., Lushington, G.H., & Butler, M.G. (2006).  Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism.  J. Med. Genet. 43(5):e21 (http://www.jmedgenet.com/cgi/content/full/43/5/e21).
  15. Bittel, D.C., Kibiryeva, N., & Butler, M.G. (2006).  Expression of four genes between chromosome 15 breakpoints BP1 and BP2 and behavioral outcomes in Prader-Willi syndrome. Pediatrics 118:e1276-1283.
  16. Zarcone, J., Napolitano, D., Peterson, C., Breidbord, J., Ferraioli, S., Caruso-Anderson, M., Holsen, L., Butler, M.G., & Thompson, T. (2007).  The relationship of compulsive behavior to academic achievement in individuals with Prader-Willi syndrome.  J. Intellect. Disabil. Res. 51:478-487.
  17. Holsen, L.M., Zarcone, J.R., Chambers, R., Butler, M.G., Bittel, D., Brooks, W.M., Thompson, T.I., & Savage, C.R. (2009).  Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome. International. Int. J. Obes (Lond). 33:273-283.
  18. Bittel, D.C., Yu, S., Newkirk, H., Kibiryeva, N., Holt, A., Butler, M.G., & Cooley, L.D. (2009). Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH. Cytogenet. Genome Res.124:113-120.
  19. Henkhaus, R.S., Bittel, D.C. & Butler, M.G. (2010). TPH2 polymorphisms and expression in Prader-Willi syndrome subjects with differing genetic subtypes. J. Neurodev. Disord. 2:144-148.
  20. Martin, L.E., Holsen, L.M., Chambers, R.J., Bruce, A.S., Brooks, W.M., Zarcone, J.R., Butler, M.G., & Savage, C.R. (2010). Neural mechanisms associated with food motivation in obese and healthy weight adults. Obesity 18:254-260.
  21. Bruce, A.S., Holsen, L.M., Chambers, R.J., Martin, L.E.,  Brooks, W.M., Zarcone, J.R., Butler, M.G., & Savage, C.R. (2010). Obese children show hyperactivation to food pictures in brain networks linked to motivation, reward, and cognitive control. Internat. J. Obes. (Lond). 34:1494-1500.
  22. Dykens, E., Roof, E., Bittel, D., & Butler, M.G. (2011). TPH2  G/T polymorphism is associated with hyperphagia in Prader-Willi syndrome. J. Child Psychol. Psychiatry. 52(5):580-587.
  23. Burnside, R.D., Pasion, R., Mikhail, F.M., Carroll, A.J., Robin, N.H., Youngs, E., Gadi, I.K., Keitges, E., Jaswaney, V.L., Papenhausen, P.R., Potluri, R., Risheg, H., Smith, J.L., Schwartz, S.,Tepperberg, J.H.. & Butler, M.G. (2011). Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: A susceptibility region for neurological dysfunction including developmental and language delay. Hum. Genet. 130(4):517-528.
  24. Butler, M.G. (2011). Prader-Willi syndrome: Obesity due to genomic imprinting. Curr. Genomics 12(3):204-215.
  25. Holsen, L.M., Savage, C.R., Martin, J.E., Bruce, A.S., Lepping, R.C., Ko, E., Brooks, W.M., Butler, M.G., Zarcone, J.R., &  Goldstein, J.M. (2012). Importance of prefrontal inhibitory circuitry in hunger and satiation: The case of Prader-Willi syndrome vs. simple obesity. Int. J. Obesity 36:638-647.
  26. Honea, R.A., Holsen, L.M., Lepping, R.J., Perea, R., Butler, M.G., Brooks, W.M. & Savage, C.R. (2012). The neuroanatomy of genetic subtype differences in Prader-Willi syndrome. Am. J. Med. Genet. B. (Neuropsychiatr Genet).159B(2):243-253.
  27. Youngs, E.L., Henkhaus, R., Hellings, J.A. & Butler, M.G. (2012). IL1RAPL1 gene deletion as a cause of X-linked mental retardation. Eur. J. Med. Genet. 55:32-36.
  28. Butler, M.G., Youngs, E.L., Roberts, J.L. & Hellings, J.A. (2012). Assessment and treatment in autism spectrum disorders: A focus on genetics and psychiatry. Autism Res. Treat. 2012:242537.
  29. Mayo-Ortega, L., Oyama-Ganiko, R., Leblanc, J., Schroeder, S.R., Brady, N., Butler, M.G., Reese, R.M., Richman, D.M., Peacock, G., Foster, J. & Marquis, J. (2012). Mass screening for severe problem behavior among infants and toddlers in Peru. J. Ment. Health Res. Intellect. Disabil. 5(3-4):246-259.
  30. Mettman, D.J., Penick, E.C., Poje, A.B., Butler, M.G.,& Manzardo, A.M. (2013). Androgen receptor gene polymorphism is associated with impulsivity and alcoholism severity in women with alcoholism. Adv. Genomics Genet., in press
  31. Schroeder, S. R., Marquis, J., Reese, R.M., Richman, D.M., Mayo-Ortega, L., Oyama-Ganiko, R., LeBlanc, J., Brady, N., Butler, M.G., Peacock, G., Foster, J., Johnson, T. & Lawrence, L. (2013). Risk factors for self-injury, aggression, and stereotyped behavior among infants and toddlers at risk for intellectual and developmental disabilities. Am. J. Intell. Dev. Disabil., in press
  32. Roberts, J.L., Hovanes, K., Dasouki, M., Manzardo, A.M. & Butler, M.G. (2013). Chromosomal microarrayanalysis of individuals with autism spectrum disorders or learning disability presenting for genetic services. Gene. 535(1):70-78


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