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Gene Discovery in Nonsyndromic Cleft Lip with Or Without Cleft Palate

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Gene Discovery in Nonsyndromic Cleft Lip with Or Without Cleft Palate The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2011 Gene Discovery in Nonsyndromic Cleft Lip with or without Cleft Palate Brett T. Chiquet Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Developmental Biology Commons, Genetics Commons, and the Molecular Genetics Commons Recommended Citation Chiquet, Brett T., "Gene Discovery in Nonsyndromic Cleft Lip with or without Cleft Palate" (2011). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 131. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/131 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. Gene Discovery in Nonsyndromic Cleft Lip with or without Cleft Palate by Brett Thomas Chiquet, B.A. APPROVED: Supervisory Professor Jacqueline T. Hecht, Ph.D. Stephen Daiger, Ph.D. Richard H. Finnell, Ph.D. Michael Gambello, M.D., Ph.D. Karen A. Storthz, Ph.D. APPROVED: Dean, The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences Gene Discovery in Nonsyndromic Cleft Lip with or without Cleft Palate A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas M.D. Anderson Cancer Center Graduate School of Biomedical Sciences In Partial Fulfillment Of the Requirements For the Degree of DOCTOR OF PHILOSOPHY by Brett Thomas Chiquet, B.A. Houston, TX May 2011 ii Acknowledgements I would first like to acknowledge my mentor, Dr. Jacqui Hecht, for having faith in me and taking a chance on this dental student who was interested in research. Her guidance and mentorship over these past years have been invaluable, and have molded every part of who I am as a scientist- from project identification and design, to grant and manuscript writing, public speaking and the art of collaboration. I am deeply appreciative of her efforts and confident that I am a better researcher because of them. To her lab (past and present) for supporting me, answering questions, helping with protocols and troubleshooting, I too am grateful, especially Drs. Shahrukh Hashmi, Karen Posey and Thomas Merritt, Francoise Coustry, Elise Bales, Huiqiu (Rachel) Wang, Tamar Powell, Candace Hurst, Elizabeth Garcia, Maria Elena Serna, Rosa Garcia, Alka Veerisetty, Qiuping Lu and Peiman Liu. I especially owe my sanity to Dr. Audrey Ester and (soon-to-be Dr.) Katelyn Weymouth. Audrey and Katelyn have been my amigos, partners in crime, sisters I never planned on, and Starbucks buddies. I would not have been able to complete this program had it not been for their support along the way. I had numerous collaborators during this process, whose help has been amazing. I’d like to thank the patients and their families for enrolling in our studies, the surgeons who send us samples, especially the Texas Cleft-Craniofacial Team, Dr. Samuel Stal and Dr. John Mulliken, Dr. Eric Swindell, Dr. Matt Warman Dr. Yukio Nakamura, Dr. Daniel Wagner and his lab, Dr. Susan Blanton and her team of analysts and Dr. Andrew Lidral. I owe a lot of gratitude to the GSBS faculty and staff, especially Dean Stancel, Drs. Tom Goka, John Wiener and Vicki Knutson, as well as Karen Weinberg, Bunny Perrez, Joy Lademora, Brenda Gaughn, and Lily D’Agostino, who all have been helpful in making sure iii that I stayed on track and graduated on time. I also owe a lot of gratitude to the Dental Branch faculty who have been supportive of my different choice of education and for making sure that it all worked out so I can complete my research studies as well as my dental studies. I am thankful for Dr. Rena D’Souza, who recruited me to the Texas Medical Center, Dr. Karen Stortz, who suggested I talk with Dr. Hecht when I was looking for a Ph.D. mentor, and Dr. Leslie Roeder, who helped me stretch out four years of dental school over seven to ensure that I had ample time to complete both degrees. My friends have helped me keep a balanced life and remember that there is life outside of school. From grad school friends, change ringing “teammates”, members of Eight Ball Surprise, St. Paul’s UMC, UTDB class of 2008 and 2011, GSBS students, and my co-officers in the Graduate Student Association- Pat Gibney, Nicole Pinaire, Chris Singh and Katelyn Weymouth- thank you all. I have been blessed to have you all in my life. Finally, I would like to thank my family. Mom, Dad, Mrs. Jan, Kayla, Grandparents, Aunts, Uncles, Cousins- thank you for supporting me these past almost thirty-something years. Thank you for always encouraging me to do my best, reach for the stars, and letting me know that I can do anything I set off to do. To Michael- thank you for being at my side throughout this whole process and supporting me and making this whole experience more enjoyable. iv Gene Discovery in Nonsyndromic Cleft Lip with or without Cleft Palate Brett Chiquet Advisor: Jacqueline T. Hecht, PhD Nonsyndromic cleft lip with or without cleft palate (NSCLP), a common, complex orofacial birth defect that affects approximately 4,000 newborns each year in the United States, is caused by both genetic and environmental factors. Orofacial clefts affect the mouth and nose, causing severe deformity of the face, which require medical, dental and speech therapies. Despite having substantial genetic liability, less than 25% of the genetic contribute to NSCLP has been identified. The studies described in this thesis were performed to identify genes that contribute to NSCLP and to demonstrate the role of these genes in normal craniofacial development. Using genome scan and candidate gene approaches, novel associations with NSCLP were identified. These include MYH9 (7 SNPs, 0.009≤p<0.05), Wnt3A (4 SNPs, 0.001≤p≤0.005), Wnt11 (2 SNPs, 0.001≤p≤0.01) and CRISPLD2 (4 SNPs, 0.001≤p<0.05). The most interesting findings were for CRISPLD2. This gene is expressed in the fused mouse palate at E17.5. In zebrafish, crispld2 localized to the craniofacial region by one day post fertilization. Morpholino knockdown of crispld2 resulted in a lower survival rates and altered neural crest cell (NCC) clustering. Because NCCs form the tissues that populate the craniofacies, this NCC abnormality resulted in cartilage abnormalities of the jaw including fewer ceratobranchial cartilages forming the lower jaw ( three pairs compared to five) and broader craniofacies compared to wild-type zebrafish. These findings suggest that the CRISPLD2 gene plays an important role in normal craniofacial development and perturbation of this gene in humans contributes to orofacial clefting. Overall, these results are important because they contribute to our v understanding of normal craniofacial development and orofacial clefting etiology, information that can be used to develop better methods to diagnose, counsel and potentially treat NSCLP patients. vi Table of Contents Approval Sheet ...................................................................................................................... i Title Page ............................................................................................................................... ii Acknowledgements ................................................................................................................ iii Abstract .................................................................................................................................. v Table of Contents ................................................................................................................... vii List of Figures ........................................................................................................................ xi List of Tables ......................................................................................................................... xii Chapter One: Craniofacial development and nonsyndromic cleft lip with or without cleft palate ................................................................................................................... 1 Introduction ....................................................................................................................... 122 Normal craniofacial development ..................................................................................... 2 Development of cleft lip and palate .................................................................................. 4 Nonsyndromic cleft lip with or without cleft palate ......................................................... 5 Etiology of NSCLP ........................................................................................................... 7 Genetic causes of NSCLP ............................................................................................ 7 Environmental causes of NSCLP ...............................................................................
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