Michael Wangler

Michael Wangler


E-mail: michael.wangler@bcm.edu

Assistant Professor, Baylor College of Medicine

B.S., University of California, San Diego, 2000
M.D., Baylor College of Medicine, 2006

Molecular mechanisms underlying rare genetic diseases using flies

Molecular and developmental mechanisms of mendelian disorders

Studies of the basic mechanisms of Mendelian diseases offer insight into general principles that underly human biology and disease. The overall long-term goal of Wangler Lab is to improve our understanding of the molecular pathogenesis of Mendelian disease by merging clinical observations, genomics and studies in model organisms particularly Drosophila melanogaster. We are currently using Drosophila to study Mendelian disorders and their underlying genetic and developmental mechanisms in two major efforts:

Model organisms and the molecular mathogenesis of mendelian disorders

Genomic sequencing is an increasingly powerful tool for identifying the genetic basis of human developmental disorders. Genomics in humans creates the unique problem of the discovery of numerous rare variants in every genome. Without a clear understanding of gene function and the role of genes in development these variants are difficult to interpret. We began developing an approach to use Drosophila to understand gene function in development and in disease. Initially our efforts involved studying novel genes by working simultaneously with a large forward genetic screen in Drosophila and a genomic database from 2,000 individuals ascertained for Mendelian disease. This rich resource allowed for numerous links between Drosophila neurobiology and Mendelian disorders (Yamamoto et al., 2014), and this approach has been an impetus for emphasizing the tremendous value of model organism and Drosophila studies (Wangler et al., 2015). We have recently developed an efficient pipeline using Drosophila melanogaster to screen many conserved genes and variant of interest from genomic sequencing studies. We have successfully applied these tools to solve cases in the Centers for Mendelian Genomics (www.mendelian.org), and we are currently applying this pipeline to developmental brain disorders such as Autism by studying genes from the Simons Simplex Collection as well as unsolved cases from the Undiagnosed Diseases Network (UDN).

Mendelian disorders of the peroxisome and organelle dynamics

Human peroxisomal disorders exhibit numerous developmental and neurological features that illustrate the overall importance of peroxisomal metabolism in multicellular organisms. We use Drosophila and human samples to study the function of peroxisomal genes.This work has identified unique human phenotypes such as a late-onset ataxia associated with PEX16 (Bacino et al., 2015) that offer new insights into particularly hypomorphic alleles. We have also studied cases of infantile encephalopathy due to DNM1L mutations (Chao et al., 2016) by using a combination of human studies and expression of the human variants in Drosophila. The study of these mutations in flies has allowed us to understand loss and gain of function alleles in peroxisomal disease and broadened our understanding of these phenotypes and their biological basis. By studying rare disorders of the peroxisome and their impact on other organelles like mitochondria we gain insight into general principles of metabolism and disease.

Selected Publications

Tompson SW, Bacino CA, Safina NP, Bober MB, Proud VK, Funari T, Wangler MF, Nevarez L, Ala-Kokko L, Wilcox WR, Eyre DR, Krakow D, Cohn DH (2010) Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene. The American Journal of Human Genetics 87:708-712.

Fruhman G, Landsverk ML, Lotze TE, Hunter JV, Wangler MF, Adesina AM, Wong LJ, Scaglia F (2011) Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation. Molecular Genetics and Metabolism 103:153-160.

Wangler MF, Reiter LT, Zimm G, Trimble-Morgan J, Wu J, Bier E (2011) Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila. Protein Cell 2:554-563.

Wangler MF, Chavan R, Hicks MJ, Nuchtern JG, Hegde M, Plon SE, Thompson PA (2013) Unusually early presentation of small-bowel adenocarcinoma in a patient with Peutz-Jeghers syndrome. Journal of Pediatric Hematology Oncology 35:323-328.

Wangler MF, Gonzaga-Jauregui C, Gambin T, Penney S, Moss T, Chopra A, Probst FJ, Xia F, Yang Y, Werlin S, Eglite I, Kornejeva L, Bacino CA, Baldridge D, Neul J, Lehman EL, Larson A, Beuten J, Muzny DM, Jhangiani S (2014) Heterozygous De Novo and inherited mutations in the Smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. PLoS Genetics 10:e1004258.

Xia F, Bainbridge MN, Tan TY, Wangler MF, Scheuerle AE, Zackai EH, Harr MH, Sutton VR, Nalam RL, Zhu W, Nash M, Ryan MM, Yaplito-Lee J, Hunter JV, Deardorff MA, Penney SJ, Beaudet AL, Plon SE, Boerwinkle EA, Lupski JR, Eng CM, Muzny DM, Yang Y, Gibbs RA (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. The American Journal of Human Genetics 94:784-789.

Faust JE, Manisundaram A, Ivanova PT, Milne SB, Summerville JB, Brown HA, Wangler M, Stern M, McNew JA (2014) Peroxisomes are required for lipid metabolism and muscle function in Drosophila melanogaster. PLoS One 9:e100213.

Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LE, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ (2014) A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell 159:200-214.

Bacino C , Chao Y-H, Seto E, Lotze T, Xia F, Moser A, Wangler MF (2015) A homozygous mutation in PEX16 identified by whole-exome sequencing ending a diagnostic odyssey. Molecular Genetics and Metabolism Reports 5:15-18.

Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Hacia JG, Bose M (2015) Peroxisome Biogenesis Disorders in the Zellweger Spectrum: an overview of current diagnosis, clinical manifestations and treatment guidelines. Molecular Genetics and Metabolism 117:313-321.

Chao Y-H, Robak L, Xia F, Koenig M, Adesina A, Bacino CA, Scaglia F, Bellen HJ, Wangler MF (2016) Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila. Human Molecular Genetics 25:1846-1856.

Contact Information

Michael Wangler, M.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
1250 Moursund St. – NRI, Suite N1050
Houston, Texas 77030, U.S.A.

Tel: (832) 822-1240
E-mail: michael.wangler@bcm.edu

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